Zebrafish: Difference between revisions

Danio rerio
	An adult female zebrafish
Conservation status
	; Least Concern (IUCN 3.1)
Scientific classification
Domain:	Eukaryota
Kingdom:	Animalia
Phylum:	Chordata
Class:	Actinopterygii
Order:	Cypriniformes
Family:	Cyprinidae
Subfamily:	Danioninae
Genus:	Danio
Species:	D. rerio
Binomial name
	Danio rerio; (F. Hamilton, 1822)
Synonyms
	Barilius rerio; Brachydanio frankei; Brachydanio rerio; Cyprinus chapalio; Cyprinus rerio; Danio frankei; Danio lineatus; Nuria rerio; Perilamopus striatus;

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The zebrafish (Danio rerio) is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio^[2] (and thus often called a "tropical fish" although both tropical and subtropical). It is also found in private ponds.

The zebrafish is an important and widely used vertebrate model organism in scientific research, for example in drug development, in particular pre-clinical development.^[3] It is also notable for its regenerative abilities,^[4] and has been modified by researchers to produce many transgenic strains.^[5]^[6]^[7]

Taxonomy

The zebrafish is a derived member of the genus Brachydanio, of the family Cyprinidae. It has a sister-group relationship with Danio aesculapii.^[8] Zebrafish are also closely related to the genus Devario, as demonstrated by a phylogenetic tree of close species.^[9] The zebrafish has often been referred to as "Danio rerio",^[10] but more recent molecular studies have suggested that it should belong to the genus Brachydanio, as Brachydanio rerio.^[11]

Range

The zebrafish is native to fresh water habitats in South Asia where it is found in India, Pakistan, Bangladesh, Nepal and Bhutan.^[1]^[12]^[13]^[14] The northern limit is in the South Himalayas, ranging from the Sutlej river basin in the Pakistan–India border region to the state of Arunachal Pradesh in northeast Indian.^[1]^[13] Its range is concentrated in the Ganges and Brahmaputra River basins, and the species was first described from Kosi River (lower Ganges basin) of India. Its range further south is more local, with scattered records from the Western and Eastern Ghats regions.^[14]^[15]^[16] It has frequently been said to occur in Myanmar (Burma), but this is entirely based on pre-1930 records and likely refers to close relatives only described later, notably Danio kyathit.^[14]^[17]^[18]^[19] Likewise, old^{[clarification needed]} records from Sri Lanka are highly questionable and remain unconfirmed.^[17]

Zebrafish have been introduced to California, Connecticut, Florida and New Mexico in the United States, presumably by deliberate release by aquarists or by escape from fish farms. The New Mexico population had been extirpated by 2003 and it is unclear if the others survive, as the last published records were decades ago.^[20] Elsewhere the species has been introduced to Colombia and Malaysia.^[13]^[21]

Habitat

Zebrafish typically inhabit moderately flowing to stagnant clear water of quite shallow depth in streams, canals, ditches, oxbow lakes, ponds and rice paddies.^[14]^[15]^[21]^[22] There is usually some vegetation, either submerged or overhanging from the banks, and the bottom is sandy, muddy or silty, often mixed with pebbles or gravel. In surveys of zebrafish locations throughout much of its Bangladeshi and Indian distribution, the water had a near-neutral to somewhat basic pH and mostly ranged from 16.5 to 34 °C (61.7–93.2 °F) in temperature.^[14]^[15]^[23] One unusually cold site was only 12.3 °C (54.1 °F) and another unusually warm site was 38.6 °C (101.5 °F), but the zebrafish still appeared healthy. The unusually cold temperature was at one of the highest known zebrafish locations at 1,576 m (5,171 ft) above sea level, although the species has been recorded to 1,795 m (5,889 ft).^[14]^[15]

Description

The zebrafish is named for the five uniform, pigmented, horizontal, blue stripes on the side of the body, which are reminiscent of a zebra's stripes, and which extend to the end of the caudal fin. Its shape is fusiform and laterally compressed, with its mouth directed upwards. The male is torpedo-shaped, with gold stripes between the blue stripes; the female has a larger, whitish belly and silver stripes instead of gold. Adult females exhibit a small genital papilla in front of the anal fin origin. The zebrafish can reach up to 4–5 cm (1.6–2.0 in) in length,^[18] although they typically are 1.8–3.7 cm (0.7–1.5 in) in the wild with some variations depending on location.^[15] Its lifespan in captivity is around two to three years, although in ideal conditions, this may be extended to over five years.^[22]^[24] In the wild it is typically an annual species.^[1]

Psychology

In 2015, a study was published about zebrafishes' capacity for episodic memory. The individuals showed a capacity to remember context with respect to objects, locations and occasions (what, when, where). Episodic memory is a capacity of explicit memory systems, typically associated with conscious experience.^[25]

Reproduction

The approximate generation time for Danio rerio is three months. A male must be present for ovulation and spawning to occur. Zebrafish are asynchronous spawners^[26] and under optimal conditions (such as food availability and favorable water parameters) can spawn successfully frequently, even on a daily basis.^[27] Females are able to spawn at intervals of two to three days, laying hundreds of eggs in each clutch. Upon release, embryonic development begins; in absence of sperm, growth stops after the first few cell divisions. Fertilized eggs almost immediately become transparent, a characteristic that makes D. rerio a convenient research model species.^[22]

The zebrafish embryo develops rapidly, with precursors to all major organs appearing within 36 hours of fertilization. The embryo begins as a yolk with a single enormous cell on top (see image, 0 h panel), which divides into two (0.75 h panel) and continues dividing until there are thousands of small cells (3.25 h panel). The cells then migrate down the sides of the yolk (8 h panel) and begin forming a head and tail (16 h panel). The tail then grows and separates from the body (24 h panel). The yolk shrinks over time because the fish uses it for food as it matures during the first few days (72 h panel). After a few months, the adult fish reaches reproductive maturity (bottom panel).

To encourage the fish to spawn, some researchers use a fish tank with a sliding bottom insert, which reduces the depth of the pool to simulate the shore of a river. Zebrafish spawn best in the morning due to their Circadian rhythms. Researchers have been able to collect 10,000 embryos in 10 minutes using this method.^[28] In particular, one pair of adult fish is capable of laying 200–300 eggs in one morning in approximately 5 to 10 at time.^[29] Male zebrafish are furthermore known to respond to more pronounced markings on females, i.e., "good stripes", but in a group, males will mate with whichever females they can find. What attracts females is not currently understood. The presence of plants, even plastic plants, also apparently encourages spawning.^[28]

Exposure to environmentally relevant concentrations of diisononyl phthalate (DINP), commonly used in a large variety of plastic items, disrupt the endocannabinoid system and thereby affect reproduction in a sex-specific manner.^[30]

Feeding

Zebrafish are omnivorous, primarily eating zooplankton, phytoplankton, insects and insect larvae, although they can eat a variety of other foods, such as worms and small crustaceans, if their preferred food sources are not readily available.^[22]

In research, adult zebrafish are often fed with brine shrimp, or paramecia.^[31]

In the aquarium

Zebrafish are hardy fish and considered good for beginner aquarists. Their enduring popularity can be attributed to their playful disposition,^[32] as well as their rapid breeding, aesthetics, cheap price and broad availability. They also do well in schools or shoals of six or more, and interact well with other fish species in the aquarium. However, they are susceptible to Oodinium or velvet disease, microsporidia (Pseudoloma neurophilia), and Mycobacterium species. Given the opportunity, adults eat hatchlings, which may be protected by separating the two groups with a net, breeding box or separate tank. In captivity, zebrafish live approximately forty-two months. Some captive zebrafish can develop a curved spine.^[33]

The zebra danio was also used to make genetically modified fish and were the first species to be sold as GloFish (fluorescent colored fish).

Strains

In late 2003, transgenic zebrafish that express green, red, and yellow fluorescent proteins became commercially available in the United States. The fluorescent strains are tradenamed GloFish; other cultivated varieties include "golden", "sandy", "longfin" and "leopard".

The leopard danio, previously known as Danio frankei, is a spotted colour morph of the zebrafish which arose due to a pigment mutation.^[34] Xanthistic forms of both the zebra and leopard pattern, along with long-finned subspecies, have been obtained via selective breeding programs for the aquarium trade.^[35]

Various transgenic and mutant strains of zebrafish were stored at the China Zebrafish Resource Center (CZRC), a non-profit organization, which was jointly supported by the Ministry of Science and Technology of China and the Chinese Academy of Sciences.^{[citation needed]}

Wild-type strains

The Zebrafish Information Network (ZFIN) provides up-to-date information about current known wild-type (WT) strains of D. rerio, some of which are listed below.^[36]

AB (AB)
AB/C32 (AB/C32)
AB/TL (AB/TL)
AB/Tuebingen (AB/TU)
C32 (C32)
Cologne (KOLN)
Darjeeling (DAR)
Ekkwill (EKW)
HK/AB (HK/AB)
HK/Sing (HK/SING)
Hong Kong (HK)
India (IND)
Indonesia (INDO)
Nadia (NA)
RIKEN WT (RW)
Singapore (SING)
SJA (SJA)
SJD (SJD)
SJD/C32 (SJD/C32)
Tuebingen (TU)
Tupfel long fin (TL)
Tupfel long fin nacre (TLN)
WIK (WIK)
WIK/AB (WIK/AB)

Hybrids

Hybrids between different Danio species may be fertile: for example, between D. rerio and D. nigrofasciatus.^[9]

Scientific research

Zebrafish chromatophores, shown here mediating background adaptation, are widely studied by scientists.

D. rerio is a common and useful scientific model organism for studies of vertebrate development and gene function. Its use as a laboratory animal was pioneered by the American molecular biologist George Streisinger and his colleagues at the University of Oregon in the 1970s and 1980s; Streisinger's zebrafish clones were among the earliest successful vertebrate clones created.^[37] Its importance has been consolidated by successful large-scale forward genetic screens (commonly referred to as the Tübingen/Boston screens). The fish has a dedicated online database of genetic, genomic, and developmental information, the Zebrafish Information Network (ZFIN). The Zebrafish International Resource Center (ZIRC) is a genetic resource repository with 29,250 alleles available for distribution to the research community. D. rerio is also one of the few fish species to have been sent into space.

Research with D. rerio has yielded advances in the fields of developmental biology, oncology,^[38] toxicology,^[39]^[40]^[41] reproductive studies, teratology, genetics, neurobiology, environmental sciences, stem cell research, regenerative medicine,^[42]^[43] muscular dystrophies^[44] and evolutionary theory.^[9]

Model characteristics

As a model biological system, the zebrafish possesses numerous advantages for scientists. Its genome has been fully sequenced, and it has well-understood, easily observable and testable developmental behaviors. Its embryonic development is very rapid, and its embryos are relatively large, robust, and transparent, and able to develop outside their mother.^[45] Furthermore, well-characterized mutant strains are readily available.

Other advantages include the species' nearly constant size during early development, which enables simple staining techniques to be used, and the fact that its two-celled embryo can be fused into a single cell to create a homozygous embryo. The zebrafish is also demonstrably similar to mammalian models and humans in toxicity testing, and exhibits a diurnal sleep cycle with similarities to mammalian sleep behavior.^[46] However, zebrafish are not a universally ideal research model; there are a number of disadvantages to their scientific use, such as the absence of a standard diet^[47] and the presence of small but important differences between zebrafish and mammals in the roles of some genes related to human disorders.^[48]^[49]

Regeneration

Zebrafish have the ability to regenerate their heart and lateral line hair cells during their larval stages.^[50]^[51] In 2011, the British Heart Foundation ran an advertising campaign publicising its intention to study the applicability of this ability to humans, stating that it aimed to raise £50 million in research funding.^[52]^[53]

Zebrafish have also been found to regenerate photoreceptor cells and retinal neurons following injury, which has been shown to be mediated by the dedifferentiation and proliferation of Müller glia.^[54] Researchers frequently amputate the dorsal and ventral tail fins and analyze their regrowth to test for mutations. It has been found that histone demethylation occurs at the site of the amputation, switching the zebrafish's cells to an "active", regenerative, stem cell-like state.^[55] In 2012, Australian scientists published a study revealing that zebrafish use a specialised protein, known as fibroblast growth factor, to ensure their spinal cords heal without glial scarring after injury.^[4] In addition, hair cells of the posterior lateral line have also been found to regenerate following damage or developmental disruption.^[51]^[56] Study of gene expression during regeneration has allowed for the identification of several important signaling pathways involved in the process, such as Wnt signaling and Fibroblast growth factor.^[56]^[57]

In probing disorders of the nervous system, including neurodegenerative diseases, movement disorders, psychiatric disorders and deafness, researchers are using the zebrafish to understand how the genetic defects underlying these conditions cause functional abnormalities in the human brain, spinal cord and sensory organs.^[58]^[59]^[60]^[61] Researchers have also studied the zebrafish to gain new insights into the complexities of human musculoskeletal diseases, such as muscular dystrophy.^[62] Another focus of zebrafish research is to understand how a gene called Hedgehog, a biological signal that underlies a number of human cancers, controls cell growth.

Genetics

Background genetics

Inbred strains and traditional outbred stocks have not been developed for laboratory zebrafish, and the genetic variability of wild-type lines among institutions may contribute to the replication crisis in biomedical research.^[63] Genetic differences in wild-type lines among populations maintained at different research institutions have been demonstrated using both Single-nucleotide polymorphisms^[64] and microsatellite analysis.^[65]

Gene expression

Due to their fast and short life cycles and relatively large clutch sizes, D. rerio or zebrafish are a useful model for genetic studies. A common reverse genetics technique is to reduce gene expression or modify splicing using Morpholino antisense technology. Morpholino oligonucleotides (MO) are stable, synthetic macromolecules that contain the same bases as DNA or RNA; by binding to complementary RNA sequences, they can reduce the expression of specific genes or block other processes from occurring on RNA. MO can be injected into one cell of an embryo after the 32-cell stage, reducing gene expression in only cells descended from that cell. However, cells in the early embryo (less than 32 cells) are interpermeable to large molecules,^[66]^[67] allowing diffusion between cells. Guidelines for using Morpholinos in zebrafish describe appropriate control strategies.^[68] Morpholinos are commonly micro injected in 500pL directly into 1-2 cell stage zebrafish embryos. The morpholino is able to integrate into most cells of the embryo.^[69]

A known problem with gene knockdowns is that, because the genome underwent a duplication after the divergence of ray-finned fishes and lobe-finned fishes, it is not always easy to silence the activity of one of the two gene paralogs reliably due to complementation by the other paralog.^[70] Despite the complications of the zebrafish genome, a number of commercially available global platforms exist for analysis of both gene expression by microarrays and promoter regulation using ChIP-on-chip.^[71]

Genome sequencing

The Wellcome Trust Sanger Institute started the zebrafish genome sequencing project in 2001, and the full genome sequence of the Tuebingen reference strain is publicly available at the National Center for Biotechnology Information (NCBI)'s Zebrafish Genome Page. The zebrafish reference genome sequence is annotated as part of the Ensembl project, and is maintained by the Genome Reference Consortium.^[72]

In 2009, researchers at the Institute of Genomics and Integrative Biology in Delhi, India, announced the sequencing of the genome of a wild zebrafish strain, containing an estimated 1.7 billion genetic letters.^[73]^[74] The genome of the wild zebrafish was sequenced at 39-fold coverage. Comparative analysis with the zebrafish reference genome revealed over 5 million single nucleotide variations and over 1.6 million insertion deletion variations. The zebrafish reference genome sequence of 1.4GB and over 26,000 protein coding genes was published by Kerstin Howe et al. in 2013.^[75]

Mitochondrial DNA

In October 2001, researchers from the University of Oklahoma published D. rerio's complete mitochondrial DNA sequence.^[76] Its length is 16,596 base pairs. This is within 100 base pairs of other related species of fish, and it is notably only 18 pairs longer than the goldfish (Carassius auratus) and 21 longer than the carp (Cyprinus carpio). Its gene order and content are identical to the common vertebrate form of mitochondrial DNA. It contains 13 protein-coding genes and a noncoding control region containing the origin of replication for the heavy strand. In between a grouping of five tRNA genes, a sequence resembling vertebrate origin of light strand replication is found. It is difficult to draw evolutionary conclusions because it is difficult to determine whether base pair changes have adaptive significance via comparisons with other vertebrates' nucleotide sequences.^[76]

Pigmentation genes

In 1999, the nacre mutation was identified in the zebrafish ortholog of the mammalian MITF transcription factor.^[77] Mutations in human MITF result in eye defects and loss of pigment, a type of Waardenburg Syndrome. In December 2005, a study of the golden strain identified the gene responsible for its unusual pigmentation as SLC24A5, a solute carrier that appeared to be required for melanin production, and confirmed its function with a Morpholino knockdown. The orthologous gene was then characterized in humans and a one base pair difference was found to strongly segregate fair-skinned Europeans and dark-skinned Africans.^[78] Zebrafish with the nacre mutation have since been bred with fish with a roy orbison (roy) mutation to make fish that have no melanophores or iridophores, and are transparent into adulthood. These fish are characterized by uniformly pigmented eyes and translucent skin.^[6]

Transgenesis

Transgenesis is a popular approach to study the function of genes in zebrafish. Construction of transgenic zebrafish is rather easy by a method using the Tol2 transposon system. Tol2 element which encodes a gene for a fully functional transposase capable of catalyzing transposition in the zebrafish germ lineage. Tol2 is the only natural DNA transposable element in vertebrates from which an autonomous member has been identified.^[79]^[80] Examples include the artificial interaction produced between LEF1 and Catenin beta-1/β-catenin/CTNNB1. Dorsky et al 2002 investigated the developmental role of Wnt by transgenically expressing a Lef1/β-catenin reporter.^[81]

Transparent adult bodies

In 2008, researchers at Boston Children's Hospital developed a new strain of zebrafish, named Casper, whose adult bodies had transparent skin.^[6] This allows for detailed visualization of cellular activity, circulation, metastasis and many other phenomena.^[6] In 2019 researchers published a crossing of a prkdc^-/- and a IL2rga^-/- strain that produced transparent, immunodeficient offspring, lacking natural killer cells as well as B- and T-cells. This strain can be adapted to 37 °C (99 °F) warm water and the absence of an immune system makes the use of patient derived xenografts possible.^[82] In January 2013, Japanese scientists genetically modified a transparent zebrafish specimen to produce a visible glow during periods of intense brain activity.^[7]

In January 2007, Chinese researchers at Fudan University genetically modified zebrafish to detect oestrogen pollution in lakes and rivers, which is linked to male infertility. The researchers cloned oestrogen-sensitive genes and injected them into the fertile eggs of zebrafish. The modified fish turned green if placed into water that was polluted by oestrogen.^[5]

RNA splicing

In 2015, researchers at Brown University discovered that 10% of zebrafish genes do not need to rely on the U2AF2 protein to initiate RNA splicing. These genes have the DNA base pairs AC and TG as repeated sequences at the ends of each intron. On the 3'ss (3' splicing site), the base pairs adenine and cytosine alternate and repeat, and on the 5'ss (5' splicing site), their complements thymine and guanine alternate and repeat as well. They found that there was less reliance on U2AF2 protein than in humans, in which the protein is required for the splicing process to occur. The pattern of repeating base pairs around introns that alters RNA secondary structure was found in other teleosts, but not in tetrapods. This indicates that an evolutionary change in tetrapods may have led to humans relying on the U2AF2 protein for RNA splicing while these genes in zebrafish undergo splicing regardless of the presence of the protein.^[83]

Orthology

D. rerio has three transferrins, all of which cluster closely with other vertebrates.^[84]

Inbreeding depression

When close relatives mate, progeny may exhibit the detrimental effects of inbreeding depression. Inbreeding depression is predominantly caused by the homozygous expression of recessive deleterious alleles.^[85] For zebra fish, inbreeding depression might be expected to be more severe in stressful environments, including those caused by anthropogenic pollution. Exposure of zebra fish to environmental stress induced by the chemical clotrimazole, an imidazole fungicide used in agriculture and in veterinary and human medicine, amplified the effects of inbreeding on key reproductive traits.^[86] Embryo viability was significantly reduced in inbred exposed fish and there was a tendency for inbred males to sire fewer offspring.

Drug discovery and development

The zebrafish and zebrafish larva is a suitable model organism for drug discovery and development. As a vertebrate with 70% genetic homology with humans,^[75] it can be predictive of human health and disease, while its small size and fast development facilitates experiments on a larger and quicker scale than with more traditional in vivo studies, including the development of higher-throughput, automated investigative tools.^[87]^[88] As demonstrated through ongoing research programmes, the zebrafish model enables researchers not only to identify genes that might underlie human disease, but also to develop novel therapeutic agents in drug discovery programmes.^[89] Zebrafish embryos have proven to be a rapid, cost-efficient, and reliable teratology assay model.^[90]

Drug screens

Drug screens in zebrafish can be used to identify novel classes of compounds with biological effects, or to repurpose existing drugs for novel uses; an example of the latter would be a screen which found that a commonly used statin (rosuvastatin) can suppress the growth of prostate cancer.^[91] To date, 65 small-molecule screens have been carried out and at least one has led to clinical trials.^[92] Within these screens, many technical challenges remain to be resolved, including differing rates of drug absorption resulting in levels of internal exposure that cannot be extrapolated from the water concentration, and high levels of natural variation between individual animals.^[92]

Toxico- or pharmacokinetics

To understand drug effects, the internal drug exposure is essential, as this drives the pharmacological effect. Translating experimental results from zebrafish to higher vertebrates (like humans) requires concentration-effect relationships, which can be derived from pharmacokinetic and pharmacodynamic analysis.^[3] Because of its small size, however, it is very challenging to quantify the internal drug exposure. Traditionally multiple blood samples would be drawn to characterize the drug concentration profile over time, but this technique remains to be developed. To date, only a single pharmacokinetic model for paracetamol has been developed in zebrafish larvae.^[93]

Computational data analysis

Using smart data analysis methods, pathophysiological and pharmacological processes can be understood and subsequently translated to higher vertebrates, including humans.^[3]^[94] An example is the use of systems pharmacology, which is the integration of systems biology and pharmacometrics. Systems biology characterizes (part of) an organism by a mathematical description of all relevant processes. These can be for example different signal transduction pathways that upon a specific signal lead to a certain response. By quantifying these processes, their behaviour in healthy and diseased situation can be understood and predicted. Pharmacometrics uses data from preclinical experiments and clinical trials to characterize the pharmacological processes that are underlying the relation between the drug dose and its response or clinical outcome. These can be for example the drug absorption in or clearance from the body, or its interaction with the target to achieve a certain effect. By quantifying these processes, their behaviour after different doses or in different patients can be understood and predicted to new doses or patients. By integrating these two fields, systems pharmacology has the potential to improve the understanding of the interaction of the drug with the biological system by mathematical quantification and subsequent prediction to new situations, like new drugs or new organisms or patients. Using these computational methods, the previously mentioned analysis of paracetamol internal exposure in zebrafish larvae showed reasonable correlation between paracetamol clearance in zebrafish with that of higher vertebrates, including humans.^[93]

Medical research

Cancer

Zebrafish have been used to make several transgenic models of cancer, including melanoma, leukemia, pancreatic cancer and hepatocellular carcinoma.^[95]^[96] Zebrafish expressing mutated forms of either the BRAF or NRAS oncogenes develop melanoma when placed onto a p53 deficient background. Histologically, these tumors strongly resemble the human disease, are fully transplantable, and exhibit large-scale genomic alterations. The BRAF melanoma model was utilized as a platform for two screens published in March 2011 in the journal Nature. In one study, the model was used as a tool to understand the functional importance of genes known to be amplified and overexpressed in human melanoma.^[97] One gene, SETDB1, markedly accelerated tumor formation in the zebrafish system, demonstrating its importance as a new melanoma oncogene. This was particularly significant because SETDB1 is known to be involved in the epigenetic regulation that is increasingly appreciated to be central to tumor cell biology.

In another study, an effort was made to therapeutically target the genetic program present in the tumor's origin neural crest cell using a chemical screening approach.^[98] This revealed that an inhibition of the DHODH protein (by a small molecule called leflunomide) prevented development of the neural crest stem cells which ultimately give rise to melanoma via interference with the process of transcriptional elongation. Because this approach would aim to target the "identity" of the melanoma cell rather than a single genetic mutation, leflunomide may have utility in treating human melanoma.^[99]

Cardiovascular disease

In cardiovascular research, the zebrafish has been used to model blood clotting, blood vessel development, heart failure, and congenital heart and kidney disease.^[100]

Immune system

In programmes of research into acute inflammation, a major underpinning process in many diseases, researchers have established a zebrafish model of inflammation, and its resolution. This approach allows detailed study of the genetic controls of inflammation and the possibility of identifying potential new drugs.^[101]

Zebrafish has been extensively used as a model organism to study vertebrate innate immunity. The innate immune system is capable of phagocytic activity by 28 to 30 h postfertilization (hpf)^[102] while adaptive immunity is not functionally mature until at least 4 weeks postfertilization.^[103]

Infectious diseases

As the immune system is relatively conserved between zebrafish and humans, many human infectious diseases can be modeled in zebrafish.^[104]^[105]^[106]^[107] The transparent early life stages are well suited for in vivo imaging and genetic dissection of host-pathogen interactions.^[108]^[109]^[110]^[111] Zebrafish models for a wide range of bacterial, viral and parasitic pathogens have already been established; for example, the zebrafish model for tuberculosis provides fundamental insights into the mechanisms of pathogenesis of mycobacteria.^[112]^[113]^[114]^[115] Furthermore, robotic technology has been developed for high-throughput antimicrobial drug screening using zebrafish infection models.^[116]^[117]

Repairing retinal damage

Another notable characteristic of the zebrafish is that it possesses four types of cone cell, with ultraviolet-sensitive cells supplementing the red, green and blue cone cell subtypes found in humans. Zebrafish can thus observe a very wide spectrum of colours. The species is also studied to better understand the development of the retina; in particular, how the cone cells of the retina become arranged into the so-called 'cone mosaic'. Zebrafish, in addition to certain other teleost fish, are particularly noted for having extreme precision of cone cell arrangement.^[118]

This study of the zebrafish's retinal characteristics has also extrapolated into medical enquiry. In 2007, researchers at University College London grew a type of zebrafish adult stem cell found in the eyes of fish and mammals that develops into neurons in the retina. These could be injected into the eye to treat diseases that damage retinal neurons—nearly every disease of the eye, including macular degeneration, glaucoma, and diabetes-related blindness. The researchers studied Müller glial cells in the eyes of humans aged from 18 months to 91 years, and were able to develop them into all types of retinal neurons. They were also able to grow them easily in the lab. The stem cells successfully migrated into diseased rats' retinas, and took on the characteristics of the surrounding neurons. The team stated that they intended to develop the same approach in humans.^[119]

Muscular dystrophies

Muscular dystrophies (MD) are a heterogeneous group of genetic disorders that cause muscle weakness, abnormal contractions and muscle wasting, often leading to premature death. Zebrafish is widely used as model organism to study muscular dystrophies.^[120] For example, the sapje (sap) mutant is the zebrafish orthologue of human Duchenne muscular dystrophy (DMD).^[121] The Machuca-Tzili and co-workers applied zebrafish to determine the role of alternative splicing factor, MBNL, in myotonic dystrophy type 1 (DM1) pathogenesis.^[122] More recently, Todd et al. described a new zebrafish model designed to explore the impact of CUG repeat expression during early development in DM1 disease.^[123] Zebrafish is also an excellent animal model to study congenital muscular dystrophies including CMD Type 1 A (CMD 1A) caused by mutation in the human laminin α2 (LAMA2) gene.^[124] The zebrafish, because of its advantages discussed above, and in particular the ability of zebrafish embryos to absorb chemicals, has become a model of choice in screening and testing new drugs against muscular distrophies.^[125]

Bone physiology and pathology

Zebrafish have been used as model organisms for bone metabolism, tissue turnover, and resorbing activity. These processes are largely evolutionary conserved. They have been used to study osteogenesis (bone formation), evaluating differentiation, matrix deposition activity, and cross-talk of skeletal cells, to create and isolate mutants modeling human bone diseases, and test new chemical compounds for the ability to revert bone defects.^[126]^[127] The larvae can be used to follow new (de novo) osteoblast formation during bone development. They start mineralising bone elements as early as 4 days post fertilisation. Recently, adult zebrafish are being used to study complex age related bone diseases such as osteoporosis and osteogenesis imperfecta.^[128] The (elasmoid) scales of zebrafish function as a protective external layer and are little bony plates made by osteoblasts. These exoskeletal structures are formed by bone matrix depositing osteoblasts and are remodeled by osteoclasts. The scales also act as the main calcium storage of the fish. They can be cultured ex-vivo (kept alive outside of the organism) in a multi-well plate, which allows manipulation with drugs and even screening for new drugs that could change bone metabolism (between osteoblasts and osteoclasts).^[128]^[129]^[130]

Diabetes

Zebrafish pancreas development is very homologous to mammals, such as mice. The signaling mechanisms and way the pancreas functions are very similar. The pancreas has an endocrine compartment, which contains a variety of cells. Pancreatic PP cells that produce polypeptides, and β-cells that produce insulin are two examples of those such cells. This structure of the pancreas, along with the glucose homeostasis system, are helpful in studying diseases, such as diabetes, that are related to the pancreas. Models for pancreas function, such as fluorescent staining of proteins, are useful in determining the processes of glucose homeostasis and the development of the pancreas. Glucose tolerance tests have been developed using zebrafish, and can now be used to test for glucose intolerance or diabetes in humans. The function of insulin are also being tested in zebrafish, which will further contribute to human medicine. The majority of work done surrounding knowledge on glucose homeostasis has come from work on zebrafish transferred to humans.^[131]

Obesity

Zebrafish have been used as a model system to study obesity, with research into both genetic obesity and over-nutrition induced obesity. Obese zebrafish, similar to obese mammals, show dysregulation of lipid controlling metabolic pathways, which leads to weight gain without normal lipid metabolism.^[131] Also like mammals, zebrafish store excess lipids in visceral, intramuscular, and subcutaneous adipose deposits. These reasons and others make zebrafish good models for studying obesity in humans and other species. Genetic obesity is usually studied in transgenic or mutated zebrafish with obesogenic genes. As an example, transgenic zerbafish with overexpressed AgRP, an endogenous melacortin antagonist, showed increased body weight and adipose deposition during growth.^[131] Though zebrafish genes may not be the exact same as human genes, these tests could provide important insight into possible genetic causes and treatments for human genetic obesity.^[131] Diet-induced obesity zebrafish models are useful, as diet can be modified from a very early age. High fat diets and general overfeeding diets both show rapid increases in adipose deposition, increased BMI, hepatosteatosis, and hypertriglyceridemia.^[131] However, the normal fat, overfed specimens are still metabolically healthy, while high-fat diet specimens are not.^[131] Understanding differences between types of feeding-induced obesity could prove useful in human treatment of obesity and related health conditions.^[131]

Environmental toxicology

Zebrafish have been used as a model system in environmental toxicology studies.^[29]

Epilepsy

Zebrafish have been used as a model system to study epilepsy. Mammalian seizures can be recapitulated molecularly, behaviorally, and electrophysiologically, using a fraction of the resources required for experiments in mammals.^[132]

References

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External links

British Association of Zebrafish Husbandry
International Zebrafish Society (IZFS)
European Society for Fish Models in Biology and Medicine (EuFishBioMed)
The Zebrafish Information Network (ZFIN)
The Zebrafish International Resource Center (ZIRC)
The European Zebrafish Resource Center (EZRC)
The China Zebrafish Resource Center (CZRC)
The Zebrafish Genome Sequencing Project at the Wellcome Trust Sanger Institute
FishMap: The Zebrafish Community Genomics Browser at the Institute of Genomics and Integrative Biology (IGIB)
WebHome Zebrafish GenomeWiki Beta Preview at the IGIB
Genome sequencing initiative at the IGIB
Danio rerio at Danios.info
Sanger Institute Zebrafish Mutation Resource
Zebrafish genome via Ensembl
FishforScience.com – using zebrafish for medical research
FishForPharma
Breeding Zebrafish
View the danRer10 genome assembly in the UCSC Genome Browser

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@@ Line 31: / Line 31: @@
 === Range ===
-The zebrafish is native to fresh water habitats in South Asia where it is found in [[India]], [[Pakistan]], [[Bangladesh]], [[Nepal]] and [[Bhutan]].<ref name="iucn status 19 November 2021" /><ref name=Petr1999>{{cite web | author=Petr, T. | year=1999 | title=Coldwater fish and fisheries in Bhutan | url=http://www.fao.org/3/x2614e/x2614e02.htm | publisher=[[FAO]] | access-date=28 March 2019}}</ref><ref name=Pritchard2001>{{cite thesis | author=Pritchard, V.L. |title=Behavior and morphogy of the zebrafish, ''Danio rerio'' | date=January 2001 |type=PhD thesis |publisher=University of Leeds}}</ref><ref name=Engeszer2007>{{cite journal | author1=Engeszer, R.E. | author2=L.B. Patterson | author3=A.A. Rao | author4=D.M. Parichy | title = Zebrafish in the wild: a review of natural history and new notes from the field | journal = Zebrafish | volume = 4 | issue = 1 | pages = 21–40 | year = 2007 | pmid = 18041940 | doi = 10.1089/zeb.2006.9997 | s2cid = 34342799 }}</ref> The northern limit is in the South [[Himalayas]], ranging from the [[Sutlej]] river basin in the Pakistan–India border region to the state of [[Arunachal Pradesh]] in northeast Indian.<ref name="iucn status 19 November 2021" /><ref name=Pritchard2001/> Its range is concentrated in the [[Ganges]] and [[Brahmaputra River]] basins, and the species was first described from [[Kosi River]] (lower Ganges basin) of India. Its range further south is more local, with scattered records from the [[Western Ghats|Western]] and [[Eastern Ghats]] regions.<ref name=Engeszer2007/><ref name=Arunachalam2013>{{cite journal | last1=Arunachalam |first1=Muthukumarasamy |last2=Raja |first2=Manickam |last3=Vijayakumar |first3=Chinnian |last4=Malaiammal |first4=Punniyam |last5=Mayden |first5=Richard L. | title = Natural history of zebrafish (''Danio rerio'') in India | journal = Zebrafish | volume = 10 | issue = 1 | pages = 1–14 | date = March 2013 | pmid = 23590398 | doi = 10.1089/zeb.2012.0803 }}</ref><ref name=UOtago>{{cite web | title=Zebrafish in the Natural Environment | url=https://www.otago.ac.nz/zebrafish/zebrafish/naturalenvironment.html | publisher=University of Otago | access-date=28 March 2019}}</ref> It has frequently been said to occur in [[Myanmar]] (Burma), but this is entirely based on pre-1930 records and likely refers to close relatives only described later, notably ''[[Danio kyathit]]''.<ref name=Engeszer2007/><ref name=Spence2006b>{{citation | author=Spence, R. |title=The behavior and ecology of the zebrafish, ''Danio rerio'' | date=December 2006 |publisher=University of Leicester}}</ref><ref name=SeriouslyFish>{{cite web | title=''Brachydanio rerio'' (Hamilton, 1822) | url=https://www.seriouslyfish.com/species/danio-rerio/ | publisher=SeriouslyFish | access-date=28 March 2019}}</ref><ref name=Fang1998>{{cite journal | author=Fang, F. | year=1998 |title=''Danio kyathit'', a new species of cyprinid species from Myitkyina, northern Myanmar |journal=Ichthyological Exploration of Freshwaters |volume=8 |issue=3 |pages=273–280 }}</ref> Likewise, old{{clarify|how old?|date=September 2020}} records from [[Sri Lanka]] are highly questionable and remain unconfirmed.<ref name=Spence2006b/>
+The zebrafish is native to fresh water habitats in South Asia where it is found in [[India]], [[Pakistan]], [[Bangladesh]], [[Nepal]] and [[Bhutan]].<ref name="iucn status 19 November 2021" /><ref name=Petr1999>{{cite web | author=Petr, T. | year=1999 | title=Coldwater fish and fisheries in Bhutan | url=http://www.fao.org/3/x2614e/x2614e02.htm | publisher=[[FAO]] | access-date=28 March 2019}}</ref><ref name=Pritchard2001>{{cite thesis | author=Pritchard, V.L. |title=Behavior and morphogy of the zebrafish, ''Danio rerio'' | date=January 2001 |type=PhD thesis |publisher=University of Leeds}}</ref><ref name=Engeszer2007>{{cite journal | vauthors = Engeszer RE, Patterson LB, Rao AA, Parichy DM | title = Zebrafish in the wild: a review of natural history and new notes from the field | journal = Zebrafish | volume = 4 | issue = 1 | pages = 21–40 | year = 2007 | pmid = 18041940 | doi = 10.1089/zeb.2006.9997 | s2cid = 34342799 }}</ref> The northern limit is in the South [[Himalayas]], ranging from the [[Sutlej]] river basin in the Pakistan–India border region to the state of [[Arunachal Pradesh]] in northeast Indian.<ref name="iucn status 19 November 2021" /><ref name=Pritchard2001/> Its range is concentrated in the [[Ganges]] and [[Brahmaputra River]] basins, and the species was first described from [[Kosi River]] (lower Ganges basin) of India. Its range further south is more local, with scattered records from the [[Western Ghats|Western]] and [[Eastern Ghats]] regions.<ref name=Engeszer2007/><ref name=Arunachalam2013>{{cite journal | vauthors = Arunachalam M, Raja M, Vijayakumar C, Malaiammal P, Mayden RL | title = Natural history of zebrafish (''Danio rerio'') in India | journal = Zebrafish | volume = 10 | issue = 1 | pages = 1–14 | date = March 2013 | pmid = 23590398 | doi = 10.1089/zeb.2012.0803 }}</ref><ref name=UOtago>{{cite web | title=Zebrafish in the Natural Environment | url=https://www.otago.ac.nz/zebrafish/zebrafish/naturalenvironment.html | publisher=University of Otago | access-date=28 March 2019}}</ref> It has frequently been said to occur in [[Myanmar]] (Burma), but this is entirely based on pre-1930 records and likely refers to close relatives only described later, notably ''[[Danio kyathit]]''.<ref name=Engeszer2007/><ref name=Spence2006b>{{citation | author=Spence, R. |title=The behavior and ecology of the zebrafish, ''Danio rerio'' | date=December 2006 |publisher=University of Leicester}}</ref><ref name=SeriouslyFish>{{cite web | title=Brachydanio rerio (Hamilton, 1822) | url=https://www.seriouslyfish.com/species/danio-rerio/ | publisher=SeriouslyFish | access-date=28 March 2019}}</ref><ref name=Fang1998>{{cite journal | vauthors = Fang F | year=1998 |title=''Danio kyathit'', a new species of cyprinid species from Myitkyina, northern Myanmar |journal=Ichthyological Exploration of Freshwaters |volume=8 |issue=3 |pages=273–280 }}</ref> Likewise, old{{clarify|how old?|date=September 2020}} records from [[Sri Lanka]] are highly questionable and remain unconfirmed.<ref name=Spence2006b/>
 Zebrafish have been [[introduced species|introduced]] to [[California]], [[Connecticut]], [[Florida]] and [[New Mexico]] in the United States, presumably by deliberate release by aquarists or by escape from [[fish farming|fish farms]]. The New Mexico population had been extirpated by 2003 and it is unclear if the others survive, as the last published records were decades ago.<ref name="NAS factsheet">{{cite web |url=https://nas.er.usgs.gov/queries/FactSheet.asp?speciesID=505 |website=Nonindigenous Aquatic Species |title=Danio rerio |publisher=[[United States Geological Survey]] |date=June 14, 2013 |access-date=July 3, 2013}}</ref> Elsewhere the species has been introduced to [[Colombia]] and [[Malaysia]].<ref name="Pritchard2001" /><ref name="fishbase">{{FishBase|genus=Danio|species=rerio||month=March|year=2019}}</ref>
@@ Line 39: / Line 39: @@
 == Description ==
-The zebrafish is named for the five uniform, pigmented, horizontal, blue stripes on the side of the body, which are reminiscent of a [[zebra]]'s stripes, and which extend to the end of the [[caudal fin]]. Its shape is [[wikt:fusiform|fusiform]] and laterally compressed, with its mouth directed upwards. The male is [[torpedo]]-shaped, with gold stripes between the blue stripes; the female has a larger, whitish belly and silver stripes instead of gold. Adult females exhibit a small [[Fish anatomy#Reproductive system|genital papilla]] in front of the [[anal fin]] origin. The zebrafish can reach up to {{cvt|4-5|cm}} in length,<ref name=SeriouslyFish/> although they typically are {{cvt|1.8-3.7|cm|1}} in the wild with some variations depending on location.<ref name=Arunachalam2013/> Its lifespan in captivity is around two to three years, although in ideal conditions, this may be extended to over five years.<ref name=beec/><ref>{{cite journal | vauthors = Gerhard GS, Kauffman EJ, Wang X, Stewart R, Moore JL, Kasales CJ, Demidenko E, Cheng KC | title = Life spans and senescent phenotypes in two strains of Zebrafish (''Danio rerio'') | journal = Experimental Gerontology | volume = 37 | issue = 8–9 | pages = 1055–1068 | year = 2002 | pmid = 12213556 | doi = 10.1016/s0531-5565(02)00088-8 | s2cid = 25092240 }}</ref> In the wild it is typically an annual species.<ref name="iucn status 19 November 2021" />
+The zebrafish is named for the five uniform, pigmented, horizontal, blue stripes on the side of the body, which are reminiscent of a [[zebra]]'s stripes, and which extend to the end of the [[caudal fin]]. Its shape is [[wikt:fusiform|fusiform]] and laterally compressed, with its mouth directed upwards. The male is [[torpedo]]-shaped, with gold stripes between the blue stripes; the female has a larger, whitish belly and silver stripes instead of gold. Adult females exhibit a small [[Fish anatomy#Reproductive system|genital papilla]] in front of the [[anal fin]] origin. The zebrafish can reach up to {{cvt|4-5|cm}} in length,<ref name=SeriouslyFish/> although they typically are {{cvt|1.8-3.7|cm|1}} in the wild with some variations depending on location.<ref name=Arunachalam2013/> Its lifespan in captivity is around two to three years, although in ideal conditions, this may be extended to over five years.<ref name=beec/><ref>{{cite journal | vauthors = Gerhard GS, Kauffman EJ, Wang X, Stewart R, Moore JL, Kasales CJ, Demidenko E, Cheng KC | display-authors = 6 | title = Life spans and senescent phenotypes in two strains of Zebrafish (''Danio rerio'') | journal = Experimental Gerontology | volume = 37 | issue = 8–9 | pages = 1055–1068 | year = 2002 | pmid = 12213556 | doi = 10.1016/s0531-5565(02)00088-8 | s2cid = 25092240 }}</ref> In the wild it is typically an annual species.<ref name="iucn status 19 November 2021" />
 == Psychology ==
-In 2015, a study was published about zebrafishes' capacity for [[episodic memory]]. The individuals showed a capacity to remember context with respect to objects, locations and occasions (what, when, where). Episodic memory is a capacity of explicit memory systems, typically associated with [[Consciousness|conscious experience]].<ref>{{cite journal | last1=Hamilton |first1=Trevor J. |last2=Myggland |first2=Allison |last3=Duperreault |first3=Erika |last4=May |first4=Zacnicte |last5=Gallup |first5=Joshua |last6=Powell |first6=Russell A. |last7=Schalomon |first7=Melike |last8=Digweed |first8=Shannon M. | title = Episodic-like memory in zebrafish | journal = Animal Cognition | volume = 19 | issue = 6 | pages = 1071–1079 | date = November 2016 | pmid = 27421709 | doi = 10.1007/s10071-016-1014-1 | s2cid = 2552608 }}</ref> The [[Mauthner cell]]s integrate a wide array of sensory stimuli to produce the [[escape reflex]]. Those stimuli are found to include the [[lateral line]] signals by McHenry et al 2009 and [[visual stimuli|visual signals]] consistent with looming objects by Temizer et al 2015, Dunn et al 2016, and Yao et al 2016.<ref name="Orger-Polavieja-2017">{{cite journal | last1=Orger | first1=Michael B. | last2=de Polavieja | first2=Gonzalo G. | title=Zebrafish Behavior: Opportunities and Challenges | journal=[[Annual Review of Neuroscience]] | publisher=[[Annual Reviews (publisher)|Annual Reviews]] | volume=40 | issue=1 | date=2017-07-25 | issn=0147-006X | doi=10.1146/annurev-neuro-071714-033857 | pages=125–147 | s2cid=46739494 | pmid=28375767}}</ref>
+In 2015, a study was published about zebrafishes' capacity for [[episodic memory]]. The individuals showed a capacity to remember context with respect to objects, locations and occasions (what, when, where). Episodic memory is a capacity of explicit memory systems, typically associated with [[Consciousness|conscious experience]].<ref>{{cite journal | vauthors = Hamilton TJ, Myggland A, Duperreault E, May Z, Gallup J, Powell RA, Schalomon M, Digweed SM | display-authors = 6 | title = Episodic-like memory in zebrafish | journal = Animal Cognition | volume = 19 | issue = 6 | pages = 1071–1079 | date = November 2016 | pmid = 27421709 | doi = 10.1007/s10071-016-1014-1 | s2cid = 2552608 }}</ref>
 == Reproduction ==
 [[File:Zebrafish Developmental Stages.tiff|thumb|upright=1.2|Stages of zebrafish development. Photos to scale except adult, which is about {{convert|2.5|cm|in|abbr=on|0}} long.]]
-The approximate [[generation time]] for ''Danio rerio'' is three months. A male must be present for [[ovulation]] and [[spawn (biology)|spawning]] to occur. Zebrafish are asynchronous spawners<ref>{{cite journal | last1=Selman|first1=Kelly|last2=Wallace|first2=Robin A.|last3=Sarka|first3=Andrew|last4=Qi|first4=Xiaoping | title = Stages of oocyte development in the zebrafish, ''Brachydanio rerio'' | journal = Journal of Morphology | volume = 218 | issue = 2 | pages = 203–224 | date = November 1993 | pmid = 29865471 | doi = 10.1002/jmor.1052180209 | s2cid = 46930941 }}</ref> and under optimal conditions (such as food availability and favorable water parameters) can spawn successfully frequently, even on a daily basis.<ref>{{cite journal | last1=Aleström|first1=Peter|last2=D’Angelo|first2=Livia|last3=Midtlyng|first3=Paul J|last4=Schorderet|first4=Daniel F|last5=Schulte-Merker|first5=Stefan|last6=Sohm|first6=Frederic|last7=Warner|first7=Susan | title = Zebrafish: Housing and husbandry recommendations | journal = Laboratory Animals | volume = 54 | issue = 3 | pages = 213–224 | date = June 2020 | pmid = 31510859 | pmc = 7301644 | doi = 10.1177/0023677219869037 }}</ref> Females are able to spawn at intervals of two to three days, laying hundreds of eggs in each [[clutch (eggs)|clutch]]. Upon release, embryonic development begins; in absence of sperm, growth stops after the first few cell divisions. Fertilized eggs almost immediately become transparent, a characteristic that makes ''D. rerio'' a convenient research [[model species]].<ref name=beec>{{cite journal | vauthors = Spence R, Gerlach G, Lawrence C, Smith C | title = The behaviour and ecology of the zebrafish, Danio rerio | journal = Biological Reviews of the Cambridge Philosophical Society | volume = 83 | issue = 1 | pages = 13–34 | date = February 2008 | pmid = 18093234 | doi = 10.1111/j.1469-185X.2007.00030.x | hdl-access = free | s2cid = 18044956 | hdl = 2381/27758 }}</ref>
+The approximate [[generation time]] for ''Danio rerio'' is three months. A male must be present for [[ovulation]] and [[spawn (biology)|spawning]] to occur. Zebrafish are asynchronous spawners<ref>{{cite journal | vauthors = Selman K, Wallace RA, Sarka A, Qi X | title = Stages of oocyte development in the zebrafish, Brachydanio rerio | journal = Journal of Morphology | volume = 218 | issue = 2 | pages = 203–224 | date = November 1993 | pmid = 29865471 | doi = 10.1002/jmor.1052180209 | s2cid = 46930941 }}</ref> and under optimal conditions (such as food availability and favorable water parameters) can spawn successfully frequently, even on a daily basis.<ref>{{cite journal | vauthors = Aleström P, D'Angelo L, Midtlyng PJ, Schorderet DF, Schulte-Merker S, Sohm F, Warner S | title = Zebrafish: Housing and husbandry recommendations | journal = Laboratory Animals | volume = 54 | issue = 3 | pages = 213–224 | date = June 2020 | pmid = 31510859 | pmc = 7301644 | doi = 10.1177/0023677219869037 }}</ref> Females are able to spawn at intervals of two to three days, laying hundreds of eggs in each [[clutch (eggs)|clutch]]. Upon release, embryonic development begins; in absence of sperm, growth stops after the first few cell divisions. Fertilized eggs almost immediately become transparent, a characteristic that makes ''D. rerio'' a convenient research [[model species]].<ref name=beec>{{cite journal | vauthors = Spence R, Gerlach G, Lawrence C, Smith C | title = The behaviour and ecology of the zebrafish, Danio rerio | journal = Biological Reviews of the Cambridge Philosophical Society | volume = 83 | issue = 1 | pages = 13–34 | date = February 2008 | pmid = 18093234 | doi = 10.1111/j.1469-185X.2007.00030.x | hdl-access = free | s2cid = 18044956 | hdl = 2381/27758 }}</ref>
 The zebrafish embryo develops rapidly, with precursors to all major organs appearing within 36 hours of fertilization.  The embryo begins as a yolk with a single enormous cell on top (see image, 0 h panel), which divides into two (0.75 h panel) and continues dividing until there are thousands of small cells (3.25 h panel).  The cells then migrate down the sides of the yolk (8 h panel) and begin forming a head and tail (16 h panel).  The tail then grows and separates from the body (24 h panel).  The yolk shrinks over time because the fish uses it for food as it matures during the first few days (72 h panel).  After a few months, the adult fish reaches reproductive maturity (bottom panel).
-To encourage the fish to spawn, some researchers use a fish tank with a sliding bottom insert, which reduces the depth of the pool to simulate the shore of a river. Zebrafish spawn best in the morning due to their [[Circadian rhythms]]. Researchers have been able to collect 10,000 embryos in 10 minutes using this method.<ref name=Spawning2012/> In particular, one pair of adult fish is capable of laying 200–300 eggs in one morning in approximately 5 to 10 at time.<ref name="Hill 6–19">{{cite journal | last1=Hill|first1=Adrian J.|last2=Teraoka|first2=Hiroki|last3=Heideman|first3=Warren|last4=Peterson|first4=Richard E. | title = Zebrafish as a model vertebrate for investigating chemical toxicity | journal = Toxicological Sciences | volume = 86 | issue = 1 | pages = 6–19 | date = July 2005 | pmid = 15703261 | doi = 10.1093/toxsci/kfi110 | doi-access = free }}</ref> Male zebrafish are furthermore known to respond to more pronounced markings on females, i.e., "good stripes", but in a group, males will mate with whichever females they can find. What attracts females is not currently understood. The presence of plants, even plastic plants, also apparently encourages spawning.<ref name=Spawning2012>{{Cite news | last=Dockser |first=Amy | name-list-style = vanc | url = https://www.wsj.com/articles/SB10001424052970203436904577154962232874998 |title=Birds Do It, Bees Do It, Even Zebrafish Do It—Just Too Little |newspaper=Wall Street Journal |date=January 13, 2012 |access-date=February 11, 2012}}</ref>
+To encourage the fish to spawn, some researchers use a fish tank with a sliding bottom insert, which reduces the depth of the pool to simulate the shore of a river. Zebrafish spawn best in the morning due to their [[Circadian rhythms]]. Researchers have been able to collect 10,000 embryos in 10 minutes using this method.<ref name=Spawning2012/> In particular, one pair of adult fish is capable of laying 200–300 eggs in one morning in approximately 5 to 10 at time.<ref name="Hill 6–19">{{cite journal | vauthors = Hill AJ, Teraoka H, Heideman W, Peterson RE | title = Zebrafish as a model vertebrate for investigating chemical toxicity | journal = Toxicological Sciences | volume = 86 | issue = 1 | pages = 6–19 | date = July 2005 | pmid = 15703261 | doi = 10.1093/toxsci/kfi110 | doi-access = free }}</ref> Male zebrafish are furthermore known to respond to more pronounced markings on females, i.e., "good stripes", but in a group, males will mate with whichever females they can find. What attracts females is not currently understood. The presence of plants, even plastic plants, also apparently encourages spawning.<ref name=Spawning2012>{{Cite news | last=Dockser |first=Amy | name-list-style = vanc | url = https://www.wsj.com/articles/SB10001424052970203436904577154962232874998 |title=Birds Do It, Bees Do It, Even Zebrafish Do It—Just Too Little |newspaper=Wall Street Journal |date=January 13, 2012 |access-date=February 11, 2012}}</ref>
-Exposure to environmentally relevant concentrations of [[diisononyl phthalate]] (DINP), commonly used in a large variety of [[plastic]] items, disrupt the [[endocannabinoid system]] and thereby affect reproduction in a sex-specific manner.<ref>{{cite journal | last1=Forner-Piquer |first1=Isabel |last2=Santangeli |first2=Stefania |last3=Maradonna |first3=Francesca |last4=Rabbito |first4=Alessandro |last5=Piscitelli |first5=Fabiana |last6=Habibi |first6=Hamid R. |last7=Di Marzo |first7=Vincenzo |last8=Carnevali |first8=Oliana | display-authors = 6 | title = Disruption of the gonadal endocannabinoid system in zebrafish exposed to diisononyl phthalate | journal = Environmental Pollution | volume = 241 | pages = 1–8 | date = October 2018 | pmid = 29793103 | doi = 10.1016/j.envpol.2018.05.007 | s2cid = 44120848 }}</ref>
+Exposure to environmentally relevant concentrations of [[diisononyl phthalate]] (DINP), commonly used in a large variety of [[plastic]] items, disrupt the [[endocannabinoid system]] and thereby affect reproduction in a sex-specific manner.<ref>{{cite journal | vauthors = Forner-Piquer I, Santangeli S, Maradonna F, Rabbito A, Piscitelli F, Habibi HR, Di Marzo V, Carnevali O | display-authors = 6 | title = Disruption of the gonadal endocannabinoid system in zebrafish exposed to diisononyl phthalate | journal = Environmental Pollution | volume = 241 | pages = 1–8 | date = October 2018 | pmid = 29793103 | doi = 10.1016/j.envpol.2018.05.007 | s2cid = 44120848 }}</ref>
 == Feeding ==
@@ Line 69: / Line 69: @@
 In late 2003, [[transgenic]] zebrafish that express [[green fluorescent protein|green]], red, and [[yellow fluorescent protein]]s became commercially available in the United States. The fluorescent strains are tradenamed [[GloFish]]; other cultivated varieties include "golden", "sandy", "longfin" and "leopard".
-The leopard danio, previously known as ''Danio frankei'', is a spotted colour [[morph (zoology)|morph]] of the zebrafish which arose due to a pigment mutation.<ref>{{cite journal | vauthors = Watanabe M, Iwashita M, Ishii M, Kurachi Y, Kawakami A, Kondo S, Okada N | title = Spot pattern of ''leopard Danio'' is caused by mutation in the zebrafish ''connexin41.8'' gene | journal = EMBO Reports | volume = 7 | issue = 9 | pages = 893–897 | date = September 2006 | pmid = 16845369 | pmc = 1559663 | doi = 10.1038/sj.embor.7400757 }}</ref> [[Xanthochromism|Xanthistic]] forms of both the zebra and leopard pattern, along with long-finned subspecies, have been obtained via selective breeding programs for the aquarium trade.<ref>{{cite book |last=Mills |first=Dick | name-list-style = vanc |title=Eyewitness Handbook: Aquarium Fish |publisher=Harper Collins |year=1993 |isbn=978-0-7322-5012-6 }}{{page needed|date=November 2012}}</ref>
+The leopard danio, previously known as ''Danio frankei'', is a spotted colour [[morph (zoology)|morph]] of the zebrafish which arose due to a pigment mutation.<ref>{{cite journal | vauthors = Watanabe M, Iwashita M, Ishii M, Kurachi Y, Kawakami A, Kondo S, Okada N | title = Spot pattern of leopard Danio is caused by mutation in the zebrafish connexin41.8 gene | journal = EMBO Reports | volume = 7 | issue = 9 | pages = 893–897 | date = September 2006 | pmid = 16845369 | pmc = 1559663 | doi = 10.1038/sj.embor.7400757 }}</ref> [[Xanthochromism|Xanthistic]] forms of both the zebra and leopard pattern, along with long-finned subspecies, have been obtained via selective breeding programs for the aquarium trade.<ref>{{cite book |last=Mills |first=Dick | name-list-style = vanc |title=Eyewitness Handbook: Aquarium Fish |publisher=Harper Collins |year=1993 |isbn=978-0-7322-5012-6 }}{{page needed|date=November 2012}}</ref>
 Various transgenic and mutant strains of zebrafish were stored at the [[China Zebrafish Resource Center]] (CZRC), a [[non-profit organization]], which was jointly supported by the [[Ministry of Science and Technology of China]] and the [[Chinese Academy of Sciences]].{{citation needed|date=March 2019}}
@@ Line 111: / Line 111: @@
 ''D. rerio'' is a common and useful scientific [[model organism]] for studies of [[vertebrate]] development and [[gene]] function. Its use as a laboratory animal was pioneered by the American [[molecular biologist]] [[George Streisinger]] and his colleagues at the [[University of Oregon]] in the 1970s and 1980s; Streisinger's zebrafish [[List of animals that have been cloned|clones]] were among the earliest successful vertebrate clones created.<ref name=StreiClone>{{cite web|url=http://www.neuro.uoregon.edu/k12/george_streisinger.html|title=In Memory of George Streisinger, "Founding Father" of Zebrafish Developmental and Genetic Research|publisher=[[University of Oregon]]|access-date=September 23, 2015}}</ref> Its importance has been consolidated by successful large-scale forward [[genetic screen]]s (commonly referred to as the Tübingen/Boston screens). The fish has a dedicated online database of genetic, genomic, and developmental information, the [[Zebrafish Information Network]] (ZFIN).  The Zebrafish International Resource Center (ZIRC) is a genetic resource repository with 29,250 [[alleles]] available for distribution to the research community. ''D. rerio'' is also one of the few fish species [[Animals in space|to have been sent into space]].
-Research with ''D. rerio'' has yielded advances in the fields of [[developmental biology]], [[oncology]],<ref>{{cite journal | vauthors = Xiang J, Yang H, Che C, Zou H, Yang H, Wei Y, Quan J, Zhang H, Yang Z, Lin S | title = Identifying tumor cell growth inhibitors by combinatorial chemistry and zebrafish assays | journal = PLOS ONE | volume = 4 | issue = 2 | pages = e4361 | year = 2009 | pmid = 19194508 | pmc = 2633036 | doi = 10.1371/journal.pone.0004361 | editor1-last = Isalan | doi-access = free | bibcode = 2009PLoSO...4.4361X | editor1-first = Mark }}</ref> [[toxicology]],<ref>{{cite journal | vauthors = Hill AJ, Teraoka H, Heideman W, Peterson RE | title = Zebrafish as a model vertebrate for investigating chemical toxicity | journal = Toxicological Sciences | volume = 86 | issue = 1 | pages = 6–19 | date = July 2005 | pmid = 15703261 | doi = 10.1093/toxsci/kfi110 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bugel SM, Tanguay RL, Planchart A | title = Zebrafish: A marvel of high-throughput biology for 21<sup>st</sup> century toxicology | journal = Current Environmental Health Reports | volume = 1 | issue = 4 | pages = 341–352 | date = September 2014 | pmid = 25678986 | pmc = 4321749 | doi = 10.1007/s40572-014-0029-5 }}</ref><ref>{{cite journal | vauthors = Dubińska-Magiera M, Daczewska M, Lewicka A, Migocka-Patrzałek M, Niedbalska-Tarnowska J, Jagla K | title = Zebrafish: A Model for the Study of Toxicants Affecting Muscle Development and Function | journal = International Journal of Molecular Sciences | volume = 17 | issue = 11 | pages = 1941 | date = November 2016 | pmid = 27869769 | pmc = 5133936 | doi = 10.3390/ijms17111941 | doi-access = free }}</ref> reproductive studies, [[teratology]], [[genetics]], [[neurobiology]], [[environmental science]]s, [[stem cell]] research, [[regenerative medicine]],<ref>{{cite journal | vauthors = Major RJ, Poss KD | title = Zebrafish Heart Regeneration as a Model for Cardiac Tissue Repair | journal = Drug Discovery Today: Disease Models | volume = 4 | issue = 4 | pages = 219–225 | year = 2007 | pmid = 19081827 | pmc = 2597874 | doi = 10.1016/j.ddmod.2007.09.002 }}</ref><ref>{{cite web|url=http://www.voanews.com/content/adult-stem-cell-research-avoids-ethical-concerns-94507429/169472.html|title=Adult Stem Cell Research Avoids Ethical Concerns|publisher=Voice of America|date=19 May 2010|access-date=21 June 2013}}</ref> [[Muscular dystrophy|muscular dystrophies]]<ref>{{cite journal | vauthors = Plantié E, Migocka-Patrzałek M, Daczewska M, Jagla K | title = Model organisms in the fight against muscular dystrophy: lessons from drosophila and Zebrafish | journal = Molecules | volume = 20 | issue = 4 | pages = 6237–6253 | date = April 2015 | pmid = 25859781 | pmc = 6272363 | doi = 10.3390/molecules20046237 | doi-access = free }}</ref> and [[evolutionary theory]].<ref name=Parichy2006/>
+Research with ''D. rerio'' has yielded advances in the fields of [[developmental biology]], [[oncology]],<ref>{{cite journal | vauthors = Xiang J, Yang H, Che C, Zou H, Yang H, Wei Y, Quan J, Zhang H, Yang Z, Lin S | display-authors = 6 | title = Identifying tumor cell growth inhibitors by combinatorial chemistry and zebrafish assays | journal = PLOS ONE | volume = 4 | issue = 2 | pages = e4361 | year = 2009 | pmid = 19194508 | pmc = 2633036 | doi = 10.1371/journal.pone.0004361 | editor1-last = Isalan | doi-access = free | bibcode = 2009PLoSO...4.4361X | editor1-first = Mark }}</ref> [[toxicology]],<ref>{{cite journal | vauthors = Hill AJ, Teraoka H, Heideman W, Peterson RE | title = Zebrafish as a model vertebrate for investigating chemical toxicity | journal = Toxicological Sciences | volume = 86 | issue = 1 | pages = 6–19 | date = July 2005 | pmid = 15703261 | doi = 10.1093/toxsci/kfi110 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bugel SM, Tanguay RL, Planchart A | title = Zebrafish: A marvel of high-throughput biology for 21<sup>st</sup> century toxicology | journal = Current Environmental Health Reports | volume = 1 | issue = 4 | pages = 341–352 | date = September 2014 | pmid = 25678986 | pmc = 4321749 | doi = 10.1007/s40572-014-0029-5 }}</ref><ref>{{cite journal | vauthors = Dubińska-Magiera M, Daczewska M, Lewicka A, Migocka-Patrzałek M, Niedbalska-Tarnowska J, Jagla K | title = Zebrafish: A Model for the Study of Toxicants Affecting Muscle Development and Function | journal = International Journal of Molecular Sciences | volume = 17 | issue = 11 | pages = 1941 | date = November 2016 | pmid = 27869769 | pmc = 5133936 | doi = 10.3390/ijms17111941 | doi-access = free }}</ref> reproductive studies, [[teratology]], [[genetics]], [[neurobiology]], [[environmental science]]s, [[stem cell]] research, [[regenerative medicine]],<ref>{{cite journal | vauthors = Major RJ, Poss KD | title = Zebrafish Heart Regeneration as a Model for Cardiac Tissue Repair | journal = Drug Discovery Today: Disease Models | volume = 4 | issue = 4 | pages = 219–225 | year = 2007 | pmid = 19081827 | pmc = 2597874 | doi = 10.1016/j.ddmod.2007.09.002 }}</ref><ref>{{cite web|url=http://www.voanews.com/content/adult-stem-cell-research-avoids-ethical-concerns-94507429/169472.html|title=Adult Stem Cell Research Avoids Ethical Concerns|publisher=Voice of America|date=19 May 2010|access-date=21 June 2013}}</ref> [[Muscular dystrophy|muscular dystrophies]]<ref>{{cite journal | vauthors = Plantié E, Migocka-Patrzałek M, Daczewska M, Jagla K | title = Model organisms in the fight against muscular dystrophy: lessons from drosophila and Zebrafish | journal = Molecules | volume = 20 | issue = 4 | pages = 6237–6253 | date = April 2015 | pmid = 25859781 | pmc = 6272363 | doi = 10.3390/molecules20046237 | doi-access = free }}</ref> and [[evolutionary theory]].<ref name=Parichy2006/>
 ===Model characteristics===
 As a model biological system, the zebrafish possesses numerous advantages for scientists. Its [[genome]] has been [[whole genome sequencing|fully sequenced]], and it has well-understood, easily observable and testable developmental behaviors. Its [[embryogenesis|embryonic development]] is very rapid, and its embryos are relatively large, robust, and transparent, and able to develop outside their mother.<ref>{{cite journal |title=The Zebrafish Exposed |first1=Ralf |last1=Dahm | name-list-style = vanc |journal=American Scientist |volume=94 |issue=5 |year=2006 |pages=446–53 |url=http://www.americanscientist.org/issues/feature/the-zebrafish-exposed |doi=10.1511/2006.61.446}}</ref> Furthermore, well-characterized mutant strains are readily available.
-Other advantages include the species' nearly constant size during early development, which enables simple [[staining]] techniques to be used, and the fact that its two-celled embryo can be fused into a single cell to create a [[homozygous]] embryo. The zebrafish is also demonstrably similar to mammalian models and humans in toxicity testing, and exhibits a diurnal sleep cycle with similarities to mammalian sleep behavior.<ref>{{cite journal | vauthors = Jones R | title = Let sleeping zebrafish lie: a new model for sleep studies | journal = PLOS Biology | volume = 5 | issue = 10 | pages = e281 | date = October 2007 | pmid = 20076649 | pmc = 2020498 | doi = 10.1371/journal.pbio.0050281 }}</ref> However, zebrafish are not a universally ideal research model; there are a number of disadvantages to their scientific use, such as the absence of a standard diet<ref>{{cite journal | vauthors = Penglase S, Moren M, Hamre K | title = Lab animals: Standardize the diet for zebrafish model | journal = Nature | volume = 491 | issue = 7424 | pages = 333 | date = November 2012 | pmid = 23151568 | doi = 10.1038/491333a | doi-access = free | bibcode = 2012Natur.491..333P }}</ref> and the presence of small but important differences between zebrafish and mammals in the roles of some genes related to human disorders.<ref>{{cite journal | vauthors = Jurynec MJ, Xia R, Mackrill JJ, Gunther D, Crawford T, Flanigan KM, Abramson JJ, Howard MT, Grunwald DJ | title = Selenoprotein N is required for ryanodine receptor calcium release channel activity in human and zebrafish muscle | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 34 | pages = 12485–12490 | date = August 2008 | pmid = 18713863 | pmc = 2527938 | doi = 10.1073/pnas.0806015105 | doi-access = free | bibcode = 2008PNAS..10512485J }}</ref><ref>{{cite journal | vauthors = Rederstorff M, Castets P, Arbogast S, Lainé J, Vassilopoulos S, Beuvin M, Dubourg O, Vignaud A, Ferry A, Krol A, Allamand V, Guicheney P, Ferreiro A, Lescure A | title = Increased muscle stress-sensitivity induced by selenoprotein N inactivation in mouse: a mammalian model for SEPN1-related myopathy | journal = PLOS ONE | volume = 6 | issue = 8 | pages = e23094 | date = 2011 | pmid = 21858002 | pmc = 3152547 | doi = 10.1371/journal.pone.0023094 | doi-access = free | bibcode = 2011PLoSO...623094R }}</ref>
+Other advantages include the species' nearly constant size during early development, which enables simple [[staining]] techniques to be used, and the fact that its two-celled embryo can be fused into a single cell to create a [[homozygous]] embryo. The zebrafish is also demonstrably similar to mammalian models and humans in toxicity testing, and exhibits a diurnal sleep cycle with similarities to mammalian sleep behavior.<ref>{{cite journal | vauthors = Jones R | title = Let sleeping zebrafish lie: a new model for sleep studies | journal = PLOS Biology | volume = 5 | issue = 10 | pages = e281 | date = October 2007 | pmid = 20076649 | pmc = 2020498 | doi = 10.1371/journal.pbio.0050281 }}</ref> However, zebrafish are not a universally ideal research model; there are a number of disadvantages to their scientific use, such as the absence of a standard diet<ref>{{cite journal | vauthors = Penglase S, Moren M, Hamre K | title = Lab animals: Standardize the diet for zebrafish model | journal = Nature | volume = 491 | issue = 7424 | pages = 333 | date = November 2012 | pmid = 23151568 | doi = 10.1038/491333a | doi-access = free | bibcode = 2012Natur.491..333P }}</ref> and the presence of small but important differences between zebrafish and mammals in the roles of some genes related to human disorders.<ref>{{cite journal | vauthors = Jurynec MJ, Xia R, Mackrill JJ, Gunther D, Crawford T, Flanigan KM, Abramson JJ, Howard MT, Grunwald DJ | display-authors = 6 | title = Selenoprotein N is required for ryanodine receptor calcium release channel activity in human and zebrafish muscle | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 34 | pages = 12485–12490 | date = August 2008 | pmid = 18713863 | pmc = 2527938 | doi = 10.1073/pnas.0806015105 | doi-access = free | bibcode = 2008PNAS..10512485J }}</ref><ref>{{cite journal | vauthors = Rederstorff M, Castets P, Arbogast S, Lainé J, Vassilopoulos S, Beuvin M, Dubourg O, Vignaud A, Ferry A, Krol A, Allamand V, Guicheney P, Ferreiro A, Lescure A | display-authors = 6 | title = Increased muscle stress-sensitivity induced by selenoprotein N inactivation in mouse: a mammalian model for SEPN1-related myopathy | journal = PLOS ONE | volume = 6 | issue = 8 | pages = e23094 | date = 2011 | pmid = 21858002 | pmc = 3152547 | doi = 10.1371/journal.pone.0023094 | doi-access = free | bibcode = 2011PLoSO...623094R }}</ref>
 ===Regeneration===
@@ Line 123: / Line 123: @@
 Zebrafish have also been found to regenerate [[photoreceptor cells]] and [[retina]]l neurons following injury, which has been shown to be mediated by the dedifferentiation and proliferation of [[Muller glia|Müller glia]].<ref>{{cite journal | vauthors = Bernardos RL, Barthel LK, Meyers JR, Raymond PA | title = Late-stage neuronal progenitors in the retina are radial Müller glia that function as retinal stem cells | journal = The Journal of Neuroscience | volume = 27 | issue = 26 | pages = 7028–7040 | date = June 2007 | pmid = 17596452 | pmc = 6672216 | doi = 10.1523/JNEUROSCI.1624-07.2007 }}</ref> Researchers frequently [[amputate]] the dorsal and ventral tail fins and analyze their regrowth to test for mutations. It has been found that [[Histone methylation|histone demethylation]] occurs at the site of the amputation, switching the zebrafish's cells to an "active", regenerative, stem cell-like state.<ref>{{cite journal | vauthors = Stewart S, Tsun ZY, Izpisua Belmonte JC | title = A histone demethylase is necessary for regeneration in zebrafish | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 47 | pages = 19889–19894 | date = November 2009 | pmid = 19897725 | pmc = 2785262 | doi = 10.1073/pnas.0904132106 | lay-url = https://www.sciencedaily.com/releases/2009/11/091102171419.htm | doi-access = free | bibcode = 2009PNAS..10619889S | lay-date = November 2, 2009 | jstor = 25593294 | lay-source = Science Daily }}</ref> In 2012, Australian scientists published a study revealing that zebrafish use a specialised [[protein]], known as [[fibroblast growth factor]], to ensure their [[spinal cord]]s heal without [[glial scar]]ring after injury.<ref name=Regen2012>{{cite journal | vauthors = Goldshmit Y, Sztal TE, Jusuf PR, Hall TE, Nguyen-Chi M, Currie PD | title = Fgf-dependent glial cell bridges facilitate spinal cord regeneration in zebrafish | journal = The Journal of Neuroscience | volume = 32 | issue = 22 | pages = 7477–7492 | date = May 2012 | pmid = 22649227 | pmc = 6703582 | doi = 10.1523/JNEUROSCI.0758-12.2012 | lay-url = http://www.sci-news.com/othersciences/biochemistry/article00366.html | lay-date = June 1, 2012 | lay-source = Sci-News.com }}</ref>  In addition, [[hair cell]]s of the posterior [[lateral line]] have also been found to regenerate following damage or developmental disruption.<ref name="autogenerated1187"/><ref name="autogenerated832">{{cite journal | vauthors = Head JR, Gacioch L, Pennisi M, Meyers JR | title = Activation of canonical Wnt/β-catenin signaling stimulates proliferation in neuromasts in the zebrafish posterior lateral line | journal = Developmental Dynamics | volume = 242 | issue = 7 | pages = 832–846 | date = July 2013 | pmid = 23606225 | doi = 10.1002/dvdy.23973 | doi-access = free }}</ref> Study of gene expression during regeneration has allowed for the identification of several important signaling pathways involved in the process, such as [[Wnt signaling]] and [[Fibroblast growth factor]].<ref name="autogenerated832"/><ref>{{cite journal | vauthors = Steiner AB, Kim T, Cabot V, Hudspeth AJ | title = Dynamic gene expression by putative hair-cell progenitors during regeneration in the zebrafish lateral line | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 14 | pages = E1393–E1401 | date = April 2014 | pmid = 24706895 | pmc = 3986164 | doi = 10.1073/pnas.1318692111 | doi-access = free | bibcode = 2014PNAS..111E1393S }}</ref>
-In probing disorders of the nervous system, including neurodegenerative diseases, movement disorders, psychiatric disorders and deafness, researchers are using the zebrafish to understand how the genetic defects underlying these conditions cause functional abnormalities in the human brain, spinal cord and sensory organs.<ref name="Kizil">{{cite journal | vauthors = Kizil C | title = Mechanisms of Pathology-Induced Neural Stem Cell Plasticity and Neural Regeneration in Adult Zebrafish Brain | journal = Current Pathobiology Reports | volume = 6 | issue = 1 | pages = 71–77 | date = January 2018 | pmid = 29938129 | pmc = 5978899 | doi = 10.1007/s40139-018-0158-x }}</ref><ref name="Cosacak">{{cite journal | vauthors = Cosacak MI, Bhattarai P, Reinhardt S, Petzold A, Dahl A, Zhang Y, Kizil C | title = Single-Cell Transcriptomics Analyses of Neural Stem Cell Heterogeneity and Contextual Plasticity in a Zebrafish Brain Model of Amyloid Toxicity | journal = Cell Reports | volume = 27 | issue = 4 | pages = 1307–1318.e3 | date = April 2019 | pmid = 31018142 | doi = 10.1016/j.celrep.2019.03.090 | doi-access = free }}</ref><ref name="Bhattarai">{{cite journal | vauthors = Bhattarai P, Cosacak MI, Mashkaryan V, Demir S, Popova SD, Govindarajan N, Brandt K, Zhang Y, Chang W, Ampatzis K, Kizil C | title = Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer's model of adult zebrafish brain | journal = PLOS Biology | volume = 18 | issue = 1 | pages = e3000585 | date = January 2020 | pmid = 31905199 | pmc = 6964913 | doi = 10.1371/journal.pbio.3000585 }}</ref><ref name="Xi">{{cite journal | vauthors = Xi Y, Noble S, Ekker M | title = Modeling neurodegeneration in zebrafish | journal = Current Neurology and Neuroscience Reports | volume = 11 | issue = 3 | pages = 274–282 | date = June 2011 | pmid = 21271309 | pmc = 3075402 | doi = 10.1007/s11910-011-0182-2 }}</ref> Researchers have also studied the zebrafish to gain new insights into the complexities of human musculoskeletal diseases, such as [[muscular dystrophy]].<ref>{{cite journal | vauthors = Bassett DI, Currie PD | title = The zebrafish as a model for muscular dystrophy and congenital myopathy | journal = Human Molecular Genetics | volume = 12 | issue = Spec No 2 | pages = R265–R270 | date = October 2003 | pmid = 14504264 | doi = 10.1093/hmg/ddg279 | doi-access = free }}</ref> Another focus of zebrafish research is to understand how a gene called [[Hedgehog signaling pathway|Hedgehog]], a biological signal that underlies a number of human cancers, controls cell growth.
+In probing disorders of the nervous system, including neurodegenerative diseases, movement disorders, psychiatric disorders and deafness, researchers are using the zebrafish to understand how the genetic defects underlying these conditions cause functional abnormalities in the human brain, spinal cord and sensory organs.<ref name="Kizil">{{cite journal | vauthors = Kizil C | title = Mechanisms of Pathology-Induced Neural Stem Cell Plasticity and Neural Regeneration in Adult Zebrafish Brain | journal = Current Pathobiology Reports | volume = 6 | issue = 1 | pages = 71–77 | date = January 2018 | pmid = 29938129 | pmc = 5978899 | doi = 10.1007/s40139-018-0158-x }}</ref><ref name="Cosacak">{{cite journal | vauthors = Cosacak MI, Bhattarai P, Reinhardt S, Petzold A, Dahl A, Zhang Y, Kizil C | title = Single-Cell Transcriptomics Analyses of Neural Stem Cell Heterogeneity and Contextual Plasticity in a Zebrafish Brain Model of Amyloid Toxicity | journal = Cell Reports | volume = 27 | issue = 4 | pages = 1307–1318.e3 | date = April 2019 | pmid = 31018142 | doi = 10.1016/j.celrep.2019.03.090 | doi-access = free }}</ref><ref name="Bhattarai">{{cite journal | vauthors = Bhattarai P, Cosacak MI, Mashkaryan V, Demir S, Popova SD, Govindarajan N, Brandt K, Zhang Y, Chang W, Ampatzis K, Kizil C | display-authors = 6 | title = Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer's model of adult zebrafish brain | journal = PLOS Biology | volume = 18 | issue = 1 | pages = e3000585 | date = January 2020 | pmid = 31905199 | pmc = 6964913 | doi = 10.1371/journal.pbio.3000585 }}</ref><ref name="Xi">{{cite journal | vauthors = Xi Y, Noble S, Ekker M | title = Modeling neurodegeneration in zebrafish | journal = Current Neurology and Neuroscience Reports | volume = 11 | issue = 3 | pages = 274–282 | date = June 2011 | pmid = 21271309 | pmc = 3075402 | doi = 10.1007/s11910-011-0182-2 }}</ref> Researchers have also studied the zebrafish to gain new insights into the complexities of human musculoskeletal diseases, such as [[muscular dystrophy]].<ref>{{cite journal | vauthors = Bassett DI, Currie PD | title = The zebrafish as a model for muscular dystrophy and congenital myopathy | journal = Human Molecular Genetics | volume = 12 | issue = Spec No 2 | pages = R265–R270 | date = October 2003 | pmid = 14504264 | doi = 10.1093/hmg/ddg279 | doi-access = free }}</ref> Another focus of zebrafish research is to understand how a gene called [[Hedgehog signaling pathway|Hedgehog]], a biological signal that underlies a number of human cancers, controls cell growth.
 ===Genetics===
 ====Background genetics====
-[[Inbred strains]] and traditional outbred stocks have not been developed for laboratory zebrafish, and the genetic variability of wild-type lines among institutions may contribute to the [[replication crisis]] in biomedical research.<ref>{{cite journal | vauthors = Crim MJ, Lawrence C | title = A fish is not a mouse: understanding differences in background genetics is critical for reproducibility | journal = Lab Animal | volume = 50 | issue = 1 | pages = 19–25 | date = January 2021 | pmid = 33268901 | doi = 10.1038/s41684-020-00683-x | s2cid = 227259359 }}</ref> Genetic differences in wild-type lines among populations maintained at different research institutions have been demonstrated using both [[Single-nucleotide polymorphism]]s<ref>{{cite journal | vauthors = Whiteley AR, Bhat A, Martins EP, Mayden RL, Arunachalam M, Uusi-Heikkilä S, Ahmed AT, Shrestha J, Clark M, Stemple D, Bernatchez L | title = Population genomics of wild and laboratory zebrafish (''Danio rerio'') | journal = Molecular Ecology | volume = 20 | issue = 20 | pages = 4259–4276 | date = October 2011 | pmid = 21923777 | pmc = 3627301 | doi = 10.1111/j.1365-294X.2011.05272.x }}</ref> and [[microsatellite]] analysis.<ref>{{cite journal | vauthors = Coe TS, Hamilton PB, Griffiths AM, Hodgson DJ, Wahab MA, Tyler CR | title = Genetic variation in strains of zebrafish (''Danio rerio'') and the implications for ecotoxicology studies | journal = Ecotoxicology | volume = 18 | issue = 1 | pages = 144–150 | date = January 2009 | pmid = 18795247 | doi = 10.1007/s10646-008-0267-0 | s2cid = 18370151 }}</ref>
+[[Inbred strains]] and traditional outbred stocks have not been developed for laboratory zebrafish, and the genetic variability of wild-type lines among institutions may contribute to the [[replication crisis]] in biomedical research.<ref>{{cite journal | vauthors = Crim MJ, Lawrence C | title = A fish is not a mouse: understanding differences in background genetics is critical for reproducibility | journal = Lab Animal | volume = 50 | issue = 1 | pages = 19–25 | date = January 2021 | pmid = 33268901 | doi = 10.1038/s41684-020-00683-x | s2cid = 227259359 }}</ref> Genetic differences in wild-type lines among populations maintained at different research institutions have been demonstrated using both [[Single-nucleotide polymorphism]]s<ref>{{cite journal | vauthors = Whiteley AR, Bhat A, Martins EP, Mayden RL, Arunachalam M, Uusi-Heikkilä S, Ahmed AT, Shrestha J, Clark M, Stemple D, Bernatchez L | display-authors = 6 | title = Population genomics of wild and laboratory zebrafish (''Danio rerio'') | journal = Molecular Ecology | volume = 20 | issue = 20 | pages = 4259–4276 | date = October 2011 | pmid = 21923777 | pmc = 3627301 | doi = 10.1111/j.1365-294X.2011.05272.x }}</ref> and [[microsatellite]] analysis.<ref>{{cite journal | vauthors = Coe TS, Hamilton PB, Griffiths AM, Hodgson DJ, Wahab MA, Tyler CR | title = Genetic variation in strains of zebrafish (''Danio rerio'') and the implications for ecotoxicology studies | journal = Ecotoxicology | volume = 18 | issue = 1 | pages = 144–150 | date = January 2009 | pmid = 18795247 | doi = 10.1007/s10646-008-0267-0 | s2cid = 18370151 }}</ref>
 ====Gene expression====
 Due to their fast and short life cycles and relatively large clutch sizes, D. ''rerio'' or zebrafish are a useful model for genetic studies. A common [[reverse genetics]] technique is to [[gene knockdown|reduce gene expression]] or modify [[Splicing (genetics)|splicing]] using [[Morpholino]] [[antisense]] technology. Morpholino [[oligonucleotide]]s (MO) are stable, synthetic [[macromolecule]]s that contain the same [[nucleoside|bases]] as DNA or RNA; by binding to complementary RNA sequences, they can reduce the [[gene expression|expression]] of specific genes or block other processes from occurring on RNA. MO can be injected into one cell of an embryo after the 32-cell stage, reducing gene expression in only cells descended from that cell. However, cells in the early embryo (less than 32 cells) are interpermeable to large molecules,<ref name=blast2>{{cite journal | vauthors = Kimmel CB, Law RD | title = Cell lineage of zebrafish blastomeres. I. Cleavage pattern and cytoplasmic bridges between cells | journal = Developmental Biology | volume = 108 | issue = 1 | pages = 78–85 | date = March 1985 | pmid = 3972182 | doi = 10.1016/0012-1606(85)90010-7 }}</ref><ref name=blast4>{{cite journal | vauthors = Kimmel CB, Law RD | title = Cell lineage of zebrafish blastomeres. III. Clonal analyses of the blastula and gastrula stages | journal = Developmental Biology | volume = 108 | issue = 1 | pages = 94–101 | date = March 1985 | pmid = 3972184 | doi = 10.1016/0012-1606(85)90012-0 }}</ref> allowing diffusion between cells. Guidelines for using Morpholinos in zebrafish describe appropriate control strategies.<ref>{{cite journal | vauthors = Stainier DY, Raz E, Lawson ND, Ekker SC, Burdine RD, Eisen JS, Ingham PW, Schulte-Merker S, Yelon D, Weinstein BM, Mullins MC, Wilson SW, Ramakrishnan L, Amacher SL, Neuhauss SC, Meng A, Mochizuki N, Panula P, Moens CB | display-authors = 6 | title = Guidelines for morpholino use in zebrafish | journal = PLOS Genetics | volume = 13 | issue = 10 | pages = e1007000 | date = October 2017 | pmid = 29049395 | pmc = 5648102 | doi = 10.1371/journal.pgen.1007000 }}</ref> Morpholinos are commonly micro injected in 500pL directly into 1-2 cell stage zebrafish embryos. The morpholino is able to integrate into most cells of the embryo.<ref>{{cite journal | vauthors = Rosen JN, Sweeney MF, Mably JD | title = Microinjection of zebrafish embryos to analyze gene function | journal = Journal of Visualized Experiments | issue = 25 | date = March 2009 | pmid = 19274045 | pmc = 2762901 | doi = 10.3791/1115 }}</ref>
-A known problem with gene knockdowns is that, because the genome underwent a [[genome#Genome evolution|duplication]] after the divergence of [[ray-finned fish]]es and [[lobe-finned fish]]es, it is not always easy to silence the activity of one of the two gene [[paralog]]s reliably due to [[Complementation (genetics)|complementation]] by the other paralog.<ref>{{cite journal | last1=Leong|first1=Ivone Un San|last2=Lan|first2=Chuan-Ching|last3=Skinner|first3=Jonathan R.|last4=Shelling|first4=Andrew N.|last5=Love|first5=Donald R. | title = In vivo testing of microRNA-mediated gene knockdown in zebrafish | journal = Journal of Biomedicine & Biotechnology | volume = 2012 | pages = 350352 | year = 2012 | pmid = 22500088 | pmc = 3303736 | doi = 10.1155/2012/350352 | publisher = Hindawi | doi-access = free }}</ref> Despite the complications of the zebrafish [[genome]], a number of commercially available global platforms exist for analysis of both gene expression by [[expression profiling|microarrays]] and promoter regulation using [[ChIP-on-chip]].<ref>{{cite journal | vauthors = Tan PK, Downey TJ, Spitznagel EL, Xu P, Fu D, Dimitrov DS, Lempicki RA, Raaka BM, Cam MC | title = Evaluation of gene expression measurements from commercial microarray platforms | journal = Nucleic Acids Research | volume = 31 | issue = 19 | pages = 5676–5684 | date = October 2003 | pmid = 14500831 | pmc = 206463 | doi = 10.1093/nar/gkg763 }}</ref>
+A known problem with gene knockdowns is that, because the genome underwent a [[genome#Genome evolution|duplication]] after the divergence of [[ray-finned fish]]es and [[lobe-finned fish]]es, it is not always easy to silence the activity of one of the two gene [[paralog]]s reliably due to [[Complementation (genetics)|complementation]] by the other paralog.<ref>{{cite journal | vauthors = Leong IU, Lan CC, Skinner JR, Shelling AN, Love DR | title = In vivo testing of microRNA-mediated gene knockdown in zebrafish | journal = Journal of Biomedicine & Biotechnology | volume = 2012 | pages = 350352 | year = 2012 | pmid = 22500088 | pmc = 3303736 | doi = 10.1155/2012/350352 | publisher = Hindawi | doi-access = free }}</ref> Despite the complications of the zebrafish [[genome]], a number of commercially available global platforms exist for analysis of both gene expression by [[expression profiling|microarrays]] and promoter regulation using [[ChIP-on-chip]].<ref>{{cite journal | vauthors = Tan PK, Downey TJ, Spitznagel EL, Xu P, Fu D, Dimitrov DS, Lempicki RA, Raaka BM, Cam MC | display-authors = 6 | title = Evaluation of gene expression measurements from commercial microarray platforms | journal = Nucleic Acids Research | volume = 31 | issue = 19 | pages = 5676–5684 | date = October 2003 | pmid = 14500831 | pmc = 206463 | doi = 10.1093/nar/gkg763 }}</ref>
 ====Genome sequencing====
@@ Line 144: / Line 144: @@
 ====Pigmentation genes====
-In 1999, the ''nacre'' mutation was identified in the zebrafish ortholog of the mammalian ''MITF'' transcription factor.<ref>{{cite journal | vauthors = Lister JA, Robertson CP, Lepage T, Johnson SL, Raible DW | title = nacre encodes a zebrafish microphthalmia-related protein that regulates neural-crest-derived pigment cell fate | journal = Development | volume = 126 | issue = 17 | pages = 3757–3767 | date = September 1999 | pmid = 10433906 | doi = 10.1242/dev.126.17.3757 }}</ref>  Mutations in human ''[[MITF]]'' result in eye defects and loss of pigment, a type of [[Waardenburg Syndrome]].  In December 2005, a study of the ''golden'' strain identified the gene responsible for its unusual pigmentation as [[SLC24A5]], a [[solute]] carrier that appeared to be required for [[melanin]] production, and confirmed its function with a Morpholino knockdown. The [[Orthologue|orthologous]] gene was then characterized in humans and a one base pair difference was found to strongly segregate fair-skinned Europeans and dark-skinned Africans.<ref>{{cite journal | vauthors = Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao W, Ning G, Makalowska I, McKeigue PM, O'donnell D, Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, Canfield VA, Cheng KC | title = SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans | journal = Science | volume = 310 | issue = 5755 | pages = 1782–1786 | date = December 2005 | pmid = 16357253 | doi = 10.1126/science.1116238 | s2cid = 2245002 | bibcode = 2005Sci...310.1782L }}</ref> <!-- this article is on fish, not on studies...This study featured on the cover of the [[academic journal]] [[Science (journal)|''Science'']] and demonstrates the power of zebrafish as a model organism in the relatively new field of [[comparative genomics]].--> Zebrafish with the ''nacre'' mutation have since been bred with fish with a ''roy orbison (roy)'' mutation to make fish that have no melanophores or iridophores, and are transparent into adulthood. These fish are characterized by uniformly pigmented eyes and translucent skin.<ref name=zviv>{{cite journal | vauthors = White RM, Sessa A, Burke C, Bowman T, LeBlanc J, Ceol C, Bourque C, Dovey M, Goessling W, Burns CE, Zon LI | title = Transparent adult zebrafish as a tool for in vivo transplantation analysis | journal = Cell Stem Cell | volume = 2 | issue = 2 | pages = 183–189 | date = February 2008 | pmid = 18371439 | pmc = 2292119 | doi = 10.1016/j.stem.2007.11.002 | lay-url = http://www.livescience.com/animals/080206-see-thru-fish.html | lay-date = February 6, 2008 | lay-source = LiveScience }}</ref>
+In 1999, the ''nacre'' mutation was identified in the zebrafish ortholog of the mammalian ''MITF'' transcription factor.<ref>{{cite journal | vauthors = Lister JA, Robertson CP, Lepage T, Johnson SL, Raible DW | title = nacre encodes a zebrafish microphthalmia-related protein that regulates neural-crest-derived pigment cell fate | journal = Development | volume = 126 | issue = 17 | pages = 3757–3767 | date = September 1999 | pmid = 10433906 | doi = 10.1242/dev.126.17.3757 }}</ref>  Mutations in human ''[[MITF]]'' result in eye defects and loss of pigment, a type of [[Waardenburg Syndrome]].  In December 2005, a study of the ''golden'' strain identified the gene responsible for its unusual pigmentation as [[SLC24A5]], a [[solute]] carrier that appeared to be required for [[melanin]] production, and confirmed its function with a Morpholino knockdown. The [[Orthologue|orthologous]] gene was then characterized in humans and a one base pair difference was found to strongly segregate fair-skinned Europeans and dark-skinned Africans.<ref>{{cite journal | vauthors = Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao W, Ning G, Makalowska I, McKeigue PM, O'donnell D, Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, Canfield VA, Cheng KC | display-authors = 6 | title = SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans | journal = Science | volume = 310 | issue = 5755 | pages = 1782–1786 | date = December 2005 | pmid = 16357253 | doi = 10.1126/science.1116238 | s2cid = 2245002 | bibcode = 2005Sci...310.1782L }}</ref> <!-- this article is on fish, not on studies...This study featured on the cover of the [[academic journal]] [[Science (journal)|''Science'']] and demonstrates the power of zebrafish as a model organism in the relatively new field of [[comparative genomics]].--> Zebrafish with the ''nacre'' mutation have since been bred with fish with a ''roy orbison (roy)'' mutation to make fish that have no melanophores or iridophores, and are transparent into adulthood. These fish are characterized by uniformly pigmented eyes and translucent skin.<ref name=zviv>{{cite journal | vauthors = White RM, Sessa A, Burke C, Bowman T, LeBlanc J, Ceol C, Bourque C, Dovey M, Goessling W, Burns CE, Zon LI | display-authors = 6 | title = Transparent adult zebrafish as a tool for in vivo transplantation analysis | journal = Cell Stem Cell | volume = 2 | issue = 2 | pages = 183–189 | date = February 2008 | pmid = 18371439 | pmc = 2292119 | doi = 10.1016/j.stem.2007.11.002 | lay-url = http://www.livescience.com/animals/080206-see-thru-fish.html | lay-date = February 6, 2008 | lay-source = LiveScience }}</ref>
 ====Transgenesis====
-[[Transgene|Transgenesis]] is a popular approach to study the function of genes in zebrafish. Construction of transgenic zebrafish is rather easy by a method using the ''Tol2'' transposon system. ''Tol2'' element which encodes a gene for a fully functional transposase capable of catalyzing transposition in the zebrafish germ lineage. ''Tol2'' is the only natural DNA transposable element in vertebrates from which an autonomous member has been identified.<ref>{{cite journal | vauthors = Kawakami K, Takeda H, Kawakami N, Kobayashi M, Matsuda N, Mishina M | title = A transposon-mediated gene trap approach identifies developmentally regulated genes in zebrafish | journal = Developmental Cell | volume = 7 | issue = 1 | pages = 133–144 | date = July 2004 | pmid = 15239961 | doi = 10.1016/j.devcel.2004.06.005 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Parinov S, Kondrichin I, Korzh V, Emelyanov A | title = Tol2 transposon-mediated enhancer trap to identify developmentally regulated zebrafish genes in vivo | journal = Developmental Dynamics | volume = 231 | issue = 2 | pages = 449–459 | date = October 2004 | pmid = 15366023 | doi = 10.1002/dvdy.20157 | doi-access = free }}</ref> Examples include the artificial interaction produced between [[Lymphoid enhancer-binding factor 1|LEF1]] and [[Catenin beta-1]]/β-catenin/''CTNNB1''. Dorsky et al 2002 investigated the developmental role of [[Wnt signaling pathway|Wnt]] by transgenically expressing a Lef1/β-catenin reporter.<ref name="Barolo-Posakony-2002">{{cite journal | last1=Barolo | first1=Scott | first2=James W. | last2=Posakony | title = Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling | journal = [[Genes & Development]] | volume = 16 | issue = 10 | pages = 1167–1181 | date = May 2002 | pmid = 12023297 | doi = 10.1101/gad.976502 | publisher = [[Cold Spring Harbor Laboratory Press]] & [[The Genetics Society]] | s2cid = 14376483 }}</ref>
+[[Transgene|Transgenesis]] is a popular approach to study the function of genes in zebrafish. Construction of transgenic zebrafish is rather easy by a method using the ''Tol2'' transposon system. ''Tol2'' element which encodes a gene for a fully functional transposase capable of catalyzing transposition in the zebrafish germ lineage. ''Tol2'' is the only natural DNA transposable element in vertebrates from which an autonomous member has been identified.<ref>{{cite journal | vauthors = Kawakami K, Takeda H, Kawakami N, Kobayashi M, Matsuda N, Mishina M | title = A transposon-mediated gene trap approach identifies developmentally regulated genes in zebrafish | journal = Developmental Cell | volume = 7 | issue = 1 | pages = 133–144 | date = July 2004 | pmid = 15239961 | doi = 10.1016/j.devcel.2004.06.005 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Parinov S, Kondrichin I, Korzh V, Emelyanov A | title = Tol2 transposon-mediated enhancer trap to identify developmentally regulated zebrafish genes in vivo | journal = Developmental Dynamics | volume = 231 | issue = 2 | pages = 449–459 | date = October 2004 | pmid = 15366023 | doi = 10.1002/dvdy.20157 | doi-access = free }}</ref> Examples include the artificial interaction produced between [[Lymphoid enhancer-binding factor 1|LEF1]] and [[Catenin beta-1]]/β-catenin/''CTNNB1''. Dorsky et al 2002 investigated the developmental role of [[Wnt signaling pathway|Wnt]] by transgenically expressing a Lef1/β-catenin reporter.<ref name="Barolo-Posakony-2002">{{cite journal | vauthors = Barolo S, Posakony JW | title = Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling | journal = Genes & Development | volume = 16 | issue = 10 | pages = 1167–1181 | date = May 2002 | pmid = 12023297 | doi = 10.1101/gad.976502 | publisher = [[Cold Spring Harbor Laboratory Press]] & [[The Genetics Society]] | s2cid = 14376483 }}</ref>
 ====Transparent adult bodies====
-In 2008, researchers at [[Boston Children's Hospital]] developed a new strain of zebrafish, named Casper, whose adult bodies had transparent skin.<ref name=zviv/> This allows for detailed visualization of cellular activity, circulation, [[metastasis]] and many other phenomena.<ref name=zviv/>  In 2019 researchers published a crossing of a ''prkdc<sup>-/-</sup>'' and a ''IL2rga<sup>-/-</sup>'' strain that produced transparent, immunodeficient offspring, lacking [[natural killer cell]]s as well as [[B cell|B]]- and [[T cell|T-cells]]. This strain can be adapted to {{convert|37|C|F}} warm water and the absence of an immune system makes the use of patient derived [[Xenotransplantation|xenografts]] possible.<ref>{{cite journal | last1=Yan | first1=Chuan | last2=Brunson | first2=Dalton C. | last3=Tang | first3=Qin | last4=Do | first4=Daniel | last5=Iftimia | first5=Nicolae A. | last6=Moore | first6=John C. | last7=Hayes | first7=Madeline N. | last8=Welker | first8=Alessandra M. | last9=Garcia | first9=Elaine G. | last10=Dubash | first10=Taronish D. | last11=Hong | first11=Xin | last12=Drapkin | first12=Benjamin J. | last13=Myers | first13=David T. | last14=Phat | first14=Sarah | last15=Volorio | first15=Angela | last16=Marvin | first16=Dieuwke L. | last17=Ligorio | first17=Matteo | last18=Dershowitz | first18=Lyle | last19=McCarthy | first19=Karin M. | last20=Karabacak | first20=Murat N. | last21=Fletcher | first21=Jonathan A. | last22=Sgroi | first22=Dennis C. | last23=Iafrate | first23=John A. | last24=Maheswaran | first24=Shyamala | last25=Dyson | first25=Nick J. | last26=Haber | first26=Daniel A. | last27=Rawls | first27=John F. | last28=Langenau | first28=David M. | title = Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish | journal = Cell | volume = 177 | issue = 7 | pages = 1903–1914.e14 | date = June 2019 | pmid = 31031007 | pmc = 6570580 | doi = 10.1016/j.cell.2019.04.004 }}</ref> In January 2013, Japanese scientists genetically modified a transparent zebrafish specimen to produce a visible glow during periods of intense brain activity.<ref name=ithinkz>{{cite web|url=http://www.popsci.com/science/article/2013-01/watch-zebrafish-think-about-food|title=Researchers Capture A Zebrafish's Thought Process On Video|website=Popular Science|date=January 31, 2013|access-date=February 4, 2013}}</ref>
+In 2008, researchers at [[Boston Children's Hospital]] developed a new strain of zebrafish, named Casper, whose adult bodies had transparent skin.<ref name=zviv/> This allows for detailed visualization of cellular activity, circulation, [[metastasis]] and many other phenomena.<ref name=zviv/>  In 2019 researchers published a crossing of a ''prkdc<sup>-/-</sup>'' and a ''IL2rga<sup>-/-</sup>'' strain that produced transparent, immunodeficient offspring, lacking [[natural killer cell]]s as well as [[B cell|B]]- and [[T cell|T-cells]]. This strain can be adapted to {{convert|37|C|F}} warm water and the absence of an immune system makes the use of patient derived [[Xenotransplantation|xenografts]] possible.<ref>{{cite journal | vauthors = Yan C, Brunson DC, Tang Q, Do D, Iftimia NA, Moore JC, Hayes MN, Welker AM, Garcia EG, Dubash TD, Hong X, Drapkin BJ, Myers DT, Phat S, Volorio A, Marvin DL, Ligorio M, Dershowitz L, McCarthy KM, Karabacak MN, Fletcher JA, Sgroi DC, Iafrate JA, Maheswaran S, Dyson NJ, Haber DA, Rawls JF, Langenau DM | display-authors = 6 | title = Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish | journal = Cell | volume = 177 | issue = 7 | pages = 1903–1914.e14 | date = June 2019 | pmid = 31031007 | pmc = 6570580 | doi = 10.1016/j.cell.2019.04.004 }}</ref> In January 2013, Japanese scientists genetically modified a transparent zebrafish specimen to produce a visible glow during periods of intense brain activity.<ref name=ithinkz>{{cite web|url=http://www.popsci.com/science/article/2013-01/watch-zebrafish-think-about-food|title=Researchers Capture A Zebrafish's Thought Process On Video|website=Popular Science|date=January 31, 2013|access-date=February 4, 2013}}</ref>
 In January 2007, Chinese researchers at [[Fudan University]] genetically modified zebrafish to detect [[oestrogen]] pollution in lakes and rivers, which is linked to male infertility. The researchers cloned oestrogen-sensitive genes and injected them into the fertile eggs of zebrafish. The modified fish turned green if placed into water that was polluted by oestrogen.<ref name=ChinaOest>[http://news.xinhuanet.com/english/2007-01/12/content_5597696.htm "Fudan scientists turn fish into estrogen alerts"]. [[Xinhua]]. January 12, 2007. Retrieved November 15, 2012.</ref>
 ====RNA splicing====
-In 2015, researchers at [[Brown University]] discovered that 10% of zebrafish genes do not need to rely on the [[U2AF2]] [[protein]] to initiate [[RNA splicing]]. These genes have the DNA base pairs AC and TG as repeated sequences at the ends of each [[intron]]. On the 3'ss (3' splicing site), the base pairs [[adenine]] and [[cytosine]] alternate and repeat, and on the 5'ss (5' splicing site), their complements [[thymine]] and [[guanine]] alternate and repeat as well. They found that there was less reliance on U2AF2 protein than in humans, in which the protein is required for the splicing process to occur. The pattern of repeating base pairs around introns that alters RNA [[nucleic acid secondary structure|secondary structure]] was found in other [[teleost]]s, but not in [[tetrapod]]s. This indicates that an evolutionary change in tetrapods may have led to humans relying on the U2AF2 protein for RNA splicing while these genes in zebrafish undergo splicing regardless of the presence of the protein.<ref name="BrownRNA">{{cite journal | vauthors = Lin CL, Taggart AJ, Lim KH, Cygan KJ, Ferraris L, Creton R, Huang YT, Fairbrother WG | title = RNA structure replaces the need for U2AF2 in splicing | journal = Genome Research | volume = 26 | issue = 1 | pages = 12–23 | date = January 2016 | pmid = 26566657 | pmc = 4691745 | doi = 10.1101/gr.181008.114 }}</ref>
+In 2015, researchers at [[Brown University]] discovered that 10% of zebrafish genes do not need to rely on the [[U2AF2]] [[protein]] to initiate [[RNA splicing]]. These genes have the DNA base pairs AC and TG as repeated sequences at the ends of each [[intron]]. On the 3'ss (3' splicing site), the base pairs [[adenine]] and [[cytosine]] alternate and repeat, and on the 5'ss (5' splicing site), their complements [[thymine]] and [[guanine]] alternate and repeat as well. They found that there was less reliance on U2AF2 protein than in humans, in which the protein is required for the splicing process to occur. The pattern of repeating base pairs around introns that alters RNA [[nucleic acid secondary structure|secondary structure]] was found in other [[teleost]]s, but not in [[tetrapod]]s. This indicates that an evolutionary change in tetrapods may have led to humans relying on the U2AF2 protein for RNA splicing while these genes in zebrafish undergo splicing regardless of the presence of the protein.<ref name="BrownRNA">{{cite journal | vauthors = Lin CL, Taggart AJ, Lim KH, Cygan KJ, Ferraris L, Creton R, Huang YT, Fairbrother WG | display-authors = 6 | title = RNA structure replaces the need for U2AF2 in splicing | journal = Genome Research | volume = 26 | issue = 1 | pages = 12–23 | date = January 2016 | pmid = 26566657 | pmc = 4691745 | doi = 10.1101/gr.181008.114 }}</ref>
 ====Orthology====
-''D. rerio'' has three [[transferrin]]s, all of which cluster closely with other [[vertebrate]]s.<ref name="Gabaldon-Koonin-2013">{{cite journal | last1=Gabaldón | first1=Toni | last2=Koonin | first2=Eugene V. | author2-link=Eugene Koonin | title = Functional and evolutionary implications of gene orthology | journal = [[Nature Reviews Genetics]] | volume = 14 | issue = 5 | pages = 360–366 | date = May 2013 | pmid = 23552219 | pmc = 5877793 | doi = 10.1038/nrg3456 | publisher = [[Nature Portfolio]] }}</ref>
+''D. rerio'' has three [[transferrin]]s, all of which cluster closely with other [[vertebrate]]s.<ref name="Gabaldon-Koonin-2013">{{cite journal | vauthors = Gabaldón T, Koonin EV | title = Functional and evolutionary implications of gene orthology | journal = Nature Reviews. Genetics | volume = 14 | issue = 5 | pages = 360–366 | date = May 2013 | pmid = 23552219 | pmc = 5877793 | doi = 10.1038/nrg3456 | publisher = [[Nature Portfolio]] | author2-link = Eugene Koonin | author3 = {{small|1=([[ORCID]] [http://orcid.org/0000-0003-3943-8299 0000-0003-3943-8299])}} }}</ref>
 ===Inbreeding depression===
-When close relatives mate, progeny may exhibit the detrimental effects of [[inbreeding depression]].  Inbreeding depression is predominantly caused by the [[Zygosity#homozygous|homozygous]] expression of recessive deleterious alleles.<ref name="pmid19834483">{{cite journal | vauthors = Charlesworth D, Willis JH | title = The genetics of inbreeding depression | journal = Nature Reviews. Genetics | volume = 10 | issue = 11 | pages = 783–796 | date = November 2009 | pmid = 19834483 | doi = 10.1038/nrg2664 | s2cid = 771357 }}</ref> For zebra fish, inbreeding depression might be expected to be more severe in stressful environments, including those caused by [[Human impact on the environment|anthropogenic pollution]]. Exposure of zebra fish to environmental stress induced by the chemical clotrimazole, an imidazole fungicide used in agriculture and in veterinary and human medicine, amplified the effects of inbreeding on key reproductive traits.<ref name="pmid23798977">{{cite journal | vauthors = Bickley LK, Brown AR, Hosken DJ, Hamilton PB, Le Page G, Paull GC, Owen SF, Tyler CR | title = Interactive effects of inbreeding and endocrine disruption on reproduction in a model laboratory fish | journal = Evolutionary Applications | volume = 6 | issue = 2 | pages = 279–289 | date = February 2013 | pmid = 23798977 | pmc = 3689353 | doi = 10.1111/j.1752-4571.2012.00288.x }}</ref> Embryo viability was significantly reduced in inbred exposed fish and there was a tendency for inbred males to sire fewer offspring.
+When close relatives mate, progeny may exhibit the detrimental effects of [[inbreeding depression]].  Inbreeding depression is predominantly caused by the [[Zygosity#homozygous|homozygous]] expression of recessive deleterious alleles.<ref name="pmid19834483">{{cite journal | vauthors = Charlesworth D, Willis JH | title = The genetics of inbreeding depression | journal = Nature Reviews. Genetics | volume = 10 | issue = 11 | pages = 783–796 | date = November 2009 | pmid = 19834483 | doi = 10.1038/nrg2664 | s2cid = 771357 }}</ref> For zebra fish, inbreeding depression might be expected to be more severe in stressful environments, including those caused by [[Human impact on the environment|anthropogenic pollution]]. Exposure of zebra fish to environmental stress induced by the chemical clotrimazole, an imidazole fungicide used in agriculture and in veterinary and human medicine, amplified the effects of inbreeding on key reproductive traits.<ref name="pmid23798977">{{cite journal | vauthors = Bickley LK, Brown AR, Hosken DJ, Hamilton PB, Le Page G, Paull GC, Owen SF, Tyler CR | display-authors = 6 | title = Interactive effects of inbreeding and endocrine disruption on reproduction in a model laboratory fish | journal = Evolutionary Applications | volume = 6 | issue = 2 | pages = 279–289 | date = February 2013 | pmid = 23798977 | pmc = 3689353 | doi = 10.1111/j.1752-4571.2012.00288.x }}</ref> Embryo viability was significantly reduced in inbred exposed fish and there was a tendency for inbred males to sire fewer offspring.
 ==Drug discovery and development==
@@ Line 167: / Line 167: @@
 [[File:Zebrafish Make a Splash in FDA Research (8614532586).jpg|thumb|FDA research used Zebrafish to show the effects of [[ketamine]] on neurological development]]
-The zebrafish and zebrafish larva is a suitable model organism for drug discovery and development. As a vertebrate with 70% genetic homology with humans,<ref name=howe2013/> it can be predictive of human health and disease, while its small size and fast development facilitates experiments on a larger and quicker scale than with more traditional [[Animal testing|in vivo]] studies, including the development of higher-throughput, automated investigative tools.<ref>{{cite journal | last1=Martin |first1=W. Kyle |last2=Tennant |first2=Alan H. |last3=Conolly |first3=Rory B. |last4=Prince |first4=Katya |last5=Stevens |first5=Joey S |last6=DeMarini |first6=David M. |last7=Martin |first7=Brandi L. |last8=Thompson |first8=Leslie C. |last9=Gilmour |first9=M. Ian |last10=Cascio |first10=Wayne E. |last11=Hays |first11=Michael D. |last12=Hazari |first12=Mehdi S. |last13=Padilla |first13=Stephanie |last14=Farraj |first14=Aimen K. | title = High-Throughput Video Processing of Heart Rate Responses in Multiple Wild-type Embryonic Zebrafish per Imaging Field | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 145 | date = January 2019 | pmid = 30644404 | pmc = 6333808 | doi = 10.1038/s41598-018-35949-5 | bibcode = 2019NatSR...9..145M }}</ref><ref>{{cite journal | vauthors = Telast1=Teixidó |first1=Elisabet |last2=Kießling |first2=Tobias R |last3=Krupp |first3=Eckart |last4=Quevedo |first4=Celia |last5=Muriana |first5=Arantza |last6=Scholz |first6=Stefan | title = Automated Morphological Feature Assessment for Zebrafish Embryo Developmental Toxicity Screens | journal = Toxicological Sciences | volume = 167 | issue = 2 | pages = 438–449 | date = February 2019 | pmid = 30295906 | pmc = 6358258 | doi = 10.1093/toxsci/kfy250 }}</ref> As demonstrated through ongoing research programmes, the zebrafish model enables researchers not only to identify genes that might underlie human disease, but also to develop novel therapeutic agents in drug discovery programmes.<ref>{{cite web |url=http://www.fishforscience.com/ |title=Fish for Science |publisher=University of Sheffield |year=2011 |access-date=March 19, 2011 }}</ref> Zebrafish embryos have proven to be a rapid, cost-efficient, and reliable [[Teratogen|teratology]] assay model.<ref>{{cite journal | vauthors = Brannen KC, Panzica-Kelly JM, Danberry TL, Augustine-Rauch KA | title = Development of a zebrafish embryo teratogenicity assay and quantitative prediction model | journal = Birth Defects Research Part B: Developmental and Reproductive Toxicology | volume = 89 | issue = 1 | pages = 66–77 | date = February 2010 | pmid = 20166227 | doi = 10.1002/bdrb.20223 }}</ref>
+The zebrafish and zebrafish larva is a suitable model organism for drug discovery and development. As a vertebrate with 70% genetic homology with humans,<ref name=howe2013/> it can be predictive of human health and disease, while its small size and fast development facilitates experiments on a larger and quicker scale than with more traditional [[Animal testing|in vivo]] studies, including the development of higher-throughput, automated investigative tools.<ref>{{cite journal | vauthors = Martin WK, Tennant AH, Conolly RB, Prince K, Stevens JS, DeMarini DM, Martin BL, Thompson LC, Gilmour MI, Cascio WE, Hays MD, Hazari MS, Padilla S, Farraj AK | display-authors = 6 | title = High-Throughput Video Processing of Heart Rate Responses in Multiple Wild-type Embryonic Zebrafish per Imaging Field | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 145 | date = January 2019 | pmid = 30644404 | pmc = 6333808 | doi = 10.1038/s41598-018-35949-5 | bibcode = 2019NatSR...9..145M }}</ref><ref>{{cite journal | vauthors = Teixidó E, Kießling TR, Krupp E, Quevedo C, Muriana A, Scholz S | title = Automated Morphological Feature Assessment for Zebrafish Embryo Developmental Toxicity Screens | journal = Toxicological Sciences | volume = 167 | issue = 2 | pages = 438–449 | date = February 2019 | pmid = 30295906 | pmc = 6358258 | doi = 10.1093/toxsci/kfy250 }}</ref> As demonstrated through ongoing research programmes, the zebrafish model enables researchers not only to identify genes that might underlie human disease, but also to develop novel therapeutic agents in drug discovery programmes.<ref>{{cite web |url=http://www.fishforscience.com/ |title=Fish for Science |publisher=University of Sheffield |year=2011 |access-date=March 19, 2011 }}</ref> Zebrafish embryos have proven to be a rapid, cost-efficient, and reliable [[Teratogen|teratology]] assay model.<ref>{{cite journal | vauthors = Brannen KC, Panzica-Kelly JM, Danberry TL, Augustine-Rauch KA | title = Development of a zebrafish embryo teratogenicity assay and quantitative prediction model | journal = Birth Defects Research. Part B, Developmental and Reproductive Toxicology | volume = 89 | issue = 1 | pages = 66–77 | date = February 2010 | pmid = 20166227 | doi = 10.1002/bdrb.20223 }}</ref>
 ===Drug screens===
@@ Line 174: / Line 174: @@
 ===Toxico- or pharmacokinetics===
 To understand drug effects, the internal drug exposure is essential, as this drives the pharmacological effect. Translating experimental results from zebrafish to higher vertebrates (like humans) requires concentration-effect relationships, which can be derived from [[pharmacokinetic]] and [[pharmacodynamic]] analysis.<ref name = vanwijk2016>{{Cite journal|last1=Van Wijk|first1=Rob C|last2=Krekels|first2=Elke HJ|last3=Hankemeier|first3=Thomas|last4=Spaink|first4=Herman P|last5=Van der Graaf|first5=Piet H | name-list-style = vanc |title=Systems pharmacology of hepatic metabolism in zebrafish larvae|journal=Drug Discovery Today: Disease Models|doi=10.1016/j.ddmod.2017.04.003|year=2017|volume=22|pages=27–34|doi-access=free}}</ref>
-Because of its small size, however, it is very challenging to quantify the internal drug exposure. Traditionally multiple blood samples would be drawn to characterize the drug concentration profile over time, but this technique remains to be developed. To date, only a single pharmacokinetic model for [[paracetamol]] has been developed in zebrafish larvae.<ref name=kantae2016>{{cite journal | vauthors = Kantae V, Krekels EH, Ordas A, González O, van Wijk RC, Harms AC, Racz PI, van der Graaf PH, Spaink HP, Hankemeier T | title = Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude | journal = Zebrafish | volume = 13 | issue = 6 | pages = 504–510 | date = December 2016 | pmid = 27632065 | pmc = 5124745 | doi = 10.1089/zeb.2016.1313 }}</ref>
+Because of its small size, however, it is very challenging to quantify the internal drug exposure. Traditionally multiple blood samples would be drawn to characterize the drug concentration profile over time, but this technique remains to be developed. To date, only a single pharmacokinetic model for [[paracetamol]] has been developed in zebrafish larvae.<ref name=kantae2016>{{cite journal | vauthors = Kantae V, Krekels EH, Ordas A, González O, van Wijk RC, Harms AC, Racz PI, van der Graaf PH, Spaink HP, Hankemeier T | display-authors = 6 | title = Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude | journal = Zebrafish | volume = 13 | issue = 6 | pages = 504–510 | date = December 2016 | pmid = 27632065 | pmc = 5124745 | doi = 10.1089/zeb.2016.1313 }}</ref>
 ===Computational data analysis===
-Using smart data analysis methods, pathophysiological and pharmacological processes can be understood and subsequently translated to higher vertebrates, including humans.<ref name = vanwijk2016/><ref name = schulthess2018>{{cite journal | last1=Schulthess|first1=Pascal|last2=Van Wijk|first2=Rob C|last3=Krekels|first3=Elke HJ|last4=Yates|first4=Thomas WT|last5=Spaink|first5=Herman P|last6=Van der Graaf|first6=Piet H | name-list-style = vanc | title = Outside-In Systems Pharmacology Combines Innovative Computational Methods With High-Throughput Whole Vertebrate Studies | journal = CPT: Pharmacometrics & Systems Pharmacology | volume = 7 | issue = 5 | pages = 285–287 | date = May 2018 | pmid = 29693322 | pmc = 5980533 | doi = 10.1002/psp4.12297 | name-list-style = vanc }}</ref> An example is the use of [[systems pharmacology]], which is the integration of [[systems biology]] and [[pharmacometrics]].
+Using smart data analysis methods, pathophysiological and pharmacological processes can be understood and subsequently translated to higher vertebrates, including humans.<ref name = vanwijk2016/><ref name = schulthess2018>{{cite journal | vauthors = Schulthess P, van Wijk RC, Krekels EH, Yates JW, Spaink HP, van der Graaf PH | title = Outside-In Systems Pharmacology Combines Innovative Computational Methods With High-Throughput Whole Vertebrate Studies | journal = CPT | volume = 7 | issue = 5 | pages = 285–287 | date = May 2018 | pmid = 29693322 | pmc = 5980533 | doi = 10.1002/psp4.12297 | name-list-style = vanc }}</ref> An example is the use of [[systems pharmacology]], which is the integration of [[systems biology]] and [[pharmacometrics]].
 Systems biology characterizes (part of) an organism by a mathematical description of all relevant processes. These can be for example different signal transduction pathways that upon a specific signal lead to a certain response. By quantifying these processes, their behaviour in healthy and diseased situation can be understood and predicted.
 Pharmacometrics uses data from preclinical experiments and [[clinical trials]] to characterize the pharmacological processes that are underlying the relation between the drug dose and its response or clinical outcome. These can be for example the drug [[absorption (pharmacology)|absorption]] in or [[clearance (pharmacology)|clearance]] from the body, or its interaction with the target to achieve a certain effect. By quantifying these processes, their behaviour after different doses or in different patients can be understood and predicted to new doses or patients.
@@ Line 186: / Line 186: @@
 ===Cancer===
-Zebrafish have been used to make several transgenic models of cancer, including [[melanoma]], [[leukemia]], [[pancreatic cancer]] and [[hepatocellular carcinoma]].<ref>{{cite journal | vauthors = Liu S, Leach SD | title = Zebrafish models for cancer | journal = Annual Review of Pathology | volume = 6 | pages = 71–93 | year = 2011 | pmid = 21261518 | doi = 10.1146/annurev-pathol-011110-130330 }}</ref><ref>{{cite web|url=https://www.sciencedaily.com/releases/2011/03/110323141852.htm|title=Zebrafish model of human melanoma reveals new cancer gene|website=Science Daily|date=March 23, 2011|access-date=April 28, 2014}}</ref> Zebrafish expressing mutated forms of either the BRAF or NRAS [[oncogene]]s develop melanoma when placed onto a p53 deficient background. [[Histology|Histologically]], these tumors strongly resemble the human disease, are fully transplantable, and exhibit large-scale genomic alterations. The BRAF melanoma model was utilized as a platform for two screens published in March 2011 in the journal ''Nature''. In one study, the model was used as a tool to understand the functional importance of genes known to be amplified and overexpressed in human melanoma.<ref>{{cite journal | vauthors = Ceol CJ, Houvras Y, Jane-Valbuena J, Bilodeau S, Orlando DA, Battisti V, Fritsch L, Lin WM, Hollmann TJ, Ferré F, Bourque C, Burke CJ, Turner L, Uong A, Johnson LA, Beroukhim R, Mermel CH, Loda M, Ait-Si-Ali S, Garraway LA, Young RA, Zon LI | title = The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset | journal = Nature | volume = 471 | issue = 7339 | pages = 513–517 | date = March 2011 | pmid = 21430779 | pmc = 3348545 | doi = 10.1038/nature09806 | bibcode = 2011Natur.471..513C }}</ref> One gene, SETDB1, markedly accelerated tumor formation in the zebrafish system, demonstrating its importance as a new melanoma oncogene. This was particularly significant because SETDB1 is known to be involved in the epigenetic regulation that is increasingly appreciated to be central to tumor cell biology.
+Zebrafish have been used to make several transgenic models of cancer, including [[melanoma]], [[leukemia]], [[pancreatic cancer]] and [[hepatocellular carcinoma]].<ref>{{cite journal | vauthors = Liu S, Leach SD | title = Zebrafish models for cancer | journal = Annual Review of Pathology | volume = 6 | pages = 71–93 | year = 2011 | pmid = 21261518 | doi = 10.1146/annurev-pathol-011110-130330 }}</ref><ref>{{cite web|url=https://www.sciencedaily.com/releases/2011/03/110323141852.htm|title=Zebrafish model of human melanoma reveals new cancer gene|website=Science Daily|date=March 23, 2011|access-date=April 28, 2014}}</ref> Zebrafish expressing mutated forms of either the BRAF or NRAS [[oncogene]]s develop melanoma when placed onto a p53 deficient background. [[Histology|Histologically]], these tumors strongly resemble the human disease, are fully transplantable, and exhibit large-scale genomic alterations. The BRAF melanoma model was utilized as a platform for two screens published in March 2011 in the journal ''Nature''. In one study, the model was used as a tool to understand the functional importance of genes known to be amplified and overexpressed in human melanoma.<ref>{{cite journal | vauthors = Ceol CJ, Houvras Y, Jane-Valbuena J, Bilodeau S, Orlando DA, Battisti V, Fritsch L, Lin WM, Hollmann TJ, Ferré F, Bourque C, Burke CJ, Turner L, Uong A, Johnson LA, Beroukhim R, Mermel CH, Loda M, Ait-Si-Ali S, Garraway LA, Young RA, Zon LI | display-authors = 6 | title = The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset | journal = Nature | volume = 471 | issue = 7339 | pages = 513–517 | date = March 2011 | pmid = 21430779 | pmc = 3348545 | doi = 10.1038/nature09806 | bibcode = 2011Natur.471..513C }}</ref> One gene, SETDB1, markedly accelerated tumor formation in the zebrafish system, demonstrating its importance as a new melanoma oncogene. This was particularly significant because SETDB1 is known to be involved in the epigenetic regulation that is increasingly appreciated to be central to tumor cell biology.
-In another study, an effort was made to therapeutically target the genetic program present in the tumor's origin [[neural crest]] cell using a chemical screening approach.<ref>{{cite journal | vauthors = White RM, Cech J, Ratanasirintrawoot S, Lin CY, Rahl PB, Burke CJ, Langdon E, Tomlinson ML, Mosher J, Kaufman C, Chen F, Long HK, Kramer M, Datta S, Neuberg D, Granter S, Young RA, Morrison S, Wheeler GN, Zon LI | title = DHODH modulates transcriptional elongation in the neural crest and melanoma | journal = Nature | volume = 471 | issue = 7339 | pages = 518–522 | date = March 2011 | pmid = 21430780 | pmc = 3759979 | doi = 10.1038/nature09882 | bibcode = 2011Natur.471..518W }}</ref> This revealed that an inhibition of the DHODH protein (by a small molecule called leflunomide) prevented development of the neural crest stem cells which ultimately give rise to melanoma via interference with the process of transcriptional elongation. Because this approach would aim to target the "identity" of the melanoma cell rather than a single genetic mutation, leflunomide may have utility in treating human melanoma.<ref>{{cite web | url = https://www.sciencedaily.com/releases/2011/03/110323141838.htm | title = Arthritis Drug Could Help Beat Melanoma Skin Cancer, Study Finds|website=Science Daily|date=March 24, 2011|access-date= November 15, 2012}}</ref>
+In another study, an effort was made to therapeutically target the genetic program present in the tumor's origin [[neural crest]] cell using a chemical screening approach.<ref>{{cite journal | vauthors = White RM, Cech J, Ratanasirintrawoot S, Lin CY, Rahl PB, Burke CJ, Langdon E, Tomlinson ML, Mosher J, Kaufman C, Chen F, Long HK, Kramer M, Datta S, Neuberg D, Granter S, Young RA, Morrison S, Wheeler GN, Zon LI | display-authors = 6 | title = DHODH modulates transcriptional elongation in the neural crest and melanoma | journal = Nature | volume = 471 | issue = 7339 | pages = 518–522 | date = March 2011 | pmid = 21430780 | pmc = 3759979 | doi = 10.1038/nature09882 | bibcode = 2011Natur.471..518W }}</ref> This revealed that an inhibition of the DHODH protein (by a small molecule called leflunomide) prevented development of the neural crest stem cells which ultimately give rise to melanoma via interference with the process of transcriptional elongation. Because this approach would aim to target the "identity" of the melanoma cell rather than a single genetic mutation, leflunomide may have utility in treating human melanoma.<ref>{{cite web | url = https://www.sciencedaily.com/releases/2011/03/110323141838.htm | title = Arthritis Drug Could Help Beat Melanoma Skin Cancer, Study Finds|website=Science Daily|date=March 24, 2011|access-date= November 15, 2012}}</ref>
 ===Cardiovascular disease===
@@ Line 196: / Line 196: @@
 In programmes of research into acute [[inflammation]], a major underpinning process in many diseases, researchers have established a zebrafish model of inflammation, and its resolution. This approach allows detailed study of the genetic controls of inflammation and the possibility of identifying potential new drugs.<ref>{{cite web|url=http://www.fishforscience.com/disease/inflammatory-disease|title=Investigating inflammatory disease using zebrafish|publisher=Fish For Science|access-date=November 15, 2012}}</ref>
-Zebrafish has been extensively used as a model organism to study vertebrate innate immunity. The innate immune system is capable of phagocytic activity by 28 to 30 h postfertilization (hpf)<ref>{{cite journal | vauthors = Le Guyader D, Redd MJ, Colucci-Guyon E, Murayama E, Kissa K, Briolat V, Mordelet E, Zapata A, Shinomiya H, Herbomel P | title = Origins and unconventional behavior of neutrophils in developing zebrafish | journal = Blood | volume = 111 | issue = 1 | pages = 132–141 | date = January 2008 | pmid = 17875807 | doi = 10.1182/blood-2007-06-095398 | s2cid = 8853409 | doi-access = free }}</ref> while adaptive immunity is not functionally mature until at least 4 weeks postfertilization.<ref>{{Cite book|title=Current Topics in Innate Immunity II|volume=946|last1=Novoa|first1=Beatriz|last2=Figueras|first2=Antonio | name-list-style = vanc |date=2012-01-01|publisher=Springer New York|isbn=9781461401056|editor-last=Lambris|editor-first=John D.|series=Advances in Experimental Medicine and Biology|pages=253–275|language=en|doi=10.1007/978-1-4614-0106-3_15|pmid = 21948373|editor-last2=Hajishengallis|editor-first2=George|hdl = 10261/44975}}</ref>
+Zebrafish has been extensively used as a model organism to study vertebrate innate immunity. The innate immune system is capable of phagocytic activity by 28 to 30 h postfertilization (hpf)<ref>{{cite journal | vauthors = Le Guyader D, Redd MJ, Colucci-Guyon E, Murayama E, Kissa K, Briolat V, Mordelet E, Zapata A, Shinomiya H, Herbomel P | display-authors = 6 | title = Origins and unconventional behavior of neutrophils in developing zebrafish | journal = Blood | volume = 111 | issue = 1 | pages = 132–141 | date = January 2008 | pmid = 17875807 | doi = 10.1182/blood-2007-06-095398 | s2cid = 8853409 | doi-access = free }}</ref> while adaptive immunity is not functionally mature until at least 4 weeks postfertilization.<ref>{{Cite book|title=Current Topics in Innate Immunity II|volume=946|last1=Novoa|first1=Beatriz|last2=Figueras|first2=Antonio | name-list-style = vanc |date=2012-01-01|publisher=Springer New York|isbn=9781461401056|editor-last=Lambris|editor-first=John D.|series=Advances in Experimental Medicine and Biology|pages=253–275|language=en|doi=10.1007/978-1-4614-0106-3_15|pmid = 21948373|editor-last2=Hajishengallis|editor-first2=George|hdl = 10261/44975}}</ref>
 ===Infectious diseases===
-As the immune system is relatively conserved between zebrafish and humans, many human infectious diseases can be modeled in zebrafish.<ref>{{cite journal | vauthors = Meeker ND, Trede NS | title = Immunology and zebrafish: spawning new models of human disease | journal = Developmental and Comparative Immunology | volume = 32 | issue = 7 | pages = 745–757 | year = 2008 | pmid = 18222541 | doi = 10.1016/j.dci.2007.11.011 }}</ref><ref>{{cite journal | vauthors = Renshaw SA, Trede NS | title = A model 450 million years in the making: zebrafish and vertebrate immunity | journal = Disease Models & Mechanisms | volume = 5 | issue = 1 | pages = 38–47 | date = January 2012 | pmid = 22228790 | pmc = 3255542 | doi = 10.1242/dmm.007138 }}</ref><ref>{{cite journal | vauthors = Meijer AH, Spaink HP | title = Host-pathogen interactions made transparent with the zebrafish model | journal = Current Drug Targets | volume = 12 | issue = 7 | pages = 1000–1017 | date = June 2011 | pmid = 21366518 | pmc = 3319919 | doi = 10.2174/138945011795677809 }}</ref><ref>{{cite journal | vauthors = van der Vaart M, Spaink HP, Meijer AH | title = Pathogen recognition and activation of the innate immune response in zebrafish | journal = Advances in Hematology | volume = 2012 | page = 159807 | year = 2012 | pmid = 22811714 | pmc = 3395205 | doi = 10.1155/2012/159807 | doi-access = free }}</ref> The transparent early life stages are well suited for ''in vivo'' imaging and genetic dissection of host-pathogen interactions.<ref>{{cite journal | vauthors = Benard EL, van der Sar AM, Ellett F, Lieschke GJ, Spaink HP, Meijer AH | title = Infection of zebrafish embryos with intracellular bacterial pathogens | journal = Journal of Visualized Experiments | issue = 61 | date = March 2012 | pmid = 22453760 | pmc = 3415172 | doi = 10.3791/3781 }}</ref><ref>{{cite journal | vauthors = Meijer AH, van der Vaart M, Spaink HP | title = Real-time imaging and genetic dissection of host-microbe interactions in zebrafish | journal = Cellular Microbiology | volume = 16 | issue = 1 | pages = 39–49 | date = January 2014 | pmid = 24188444 | doi = 10.1111/cmi.12236 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Torraca V, Masud S, Spaink HP, Meijer AH | title = Macrophage-pathogen interactions in infectious diseases: new therapeutic insights from the zebrafish host model | journal = Disease Models & Mechanisms | volume = 7 | issue = 7 | pages = 785–797 | date = July 2014 | pmid = 24973749 | pmc = 4073269 | doi = 10.1242/dmm.015594 }}</ref><ref>{{cite journal | vauthors = Levraud JP, Palha N, Langevin C, Boudinot P | title = Through the looking glass: witnessing host-virus interplay in zebrafish | journal = Trends in Microbiology | volume = 22 | issue = 9 | pages = 490–497 | date = September 2014 | pmid = 24865811 | doi = 10.1016/j.tim.2014.04.014 }}</ref> Zebrafish models for a wide range of bacterial, viral and parasitic pathogens have already been established; for example, the zebrafish model for tuberculosis provides fundamental insights into the mechanisms of pathogenesis of mycobacteria.<ref>{{Cite book | vauthors = Ramakrishnan L | volume = 783 | pages = 251–66 | year = 2013 | pmid = 23468113 | doi = 10.1007/978-1-4614-6111-1_13 | isbn = 978-1-4614-6110-4 | series = Advances in Experimental Medicine and Biology | title = The New Paradigm of Immunity to Tuberculosis | chapter = Looking Within the Zebrafish to Understand the Tuberculous Granuloma }}</ref><ref>{{cite journal | vauthors = Ramakrishnan L | title = The zebrafish guide to tuberculosis immunity and treatment | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 78 | pages = 179–192 | year = 2013 | pmid = 24643219 | doi = 10.1101/sqb.2013.78.023283 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cronan MR, Tobin DM | title = Fit for consumption: zebrafish as a model for tuberculosis | journal = Disease Models & Mechanisms | volume = 7 | issue = 7 | pages = 777–784 | date = July 2014 | pmid = 24973748 | pmc = 4073268 | doi = 10.1242/dmm.016089 }}</ref><ref>{{cite journal | vauthors = Meijer AH | title = Protection and pathology in TB: learning from the zebrafish model | journal = Seminars in Immunopathology | volume = 38 | issue = 2 | pages = 261–273 | date = March 2016 | pmid = 26324465 | pmc = 4779130 | doi = 10.1007/s00281-015-0522-4 }}</ref> Furthermore, robotic technology has been developed for  high-throughput antimicrobial drug screening using zebrafish infection models.<ref>{{cite journal | vauthors = Spaink HP, Cui C, Wiweger MI, Jansen HJ, Veneman WJ, Marín-Juez R, de Sonneville J, Ordas A, Torraca V, van der Ent W, Leenders WP, Meijer AH, Snaar-Jagalska BE, Dirks RP | title = Robotic injection of zebrafish embryos for high-throughput screening in disease models | journal = Methods | volume = 62 | issue = 3 | pages = 246–254 | date = August 2013 | pmid = 23769806 | doi = 10.1016/j.ymeth.2013.06.002 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Veneman WJ, Marín-Juez R, de Sonneville J, Ordas A, Jong-Raadsen S, Meijer AH, Spaink HP | title = Establishment and optimization of a high throughput setup to study Staphylococcus epidermidis and Mycobacterium marinum infection as a model for drug discovery | journal = Journal of Visualized Experiments | volume = 88 | issue = 88 | pages = e51649 | date = June 2014 | pmid = 24998295 | pmc = 4206090 | doi = 10.3791/51649 }}</ref>
+As the immune system is relatively conserved between zebrafish and humans, many human infectious diseases can be modeled in zebrafish.<ref>{{cite journal | vauthors = Meeker ND, Trede NS | title = Immunology and zebrafish: spawning new models of human disease | journal = Developmental and Comparative Immunology | volume = 32 | issue = 7 | pages = 745–757 | year = 2008 | pmid = 18222541 | doi = 10.1016/j.dci.2007.11.011 }}</ref><ref>{{cite journal | vauthors = Renshaw SA, Trede NS | title = A model 450 million years in the making: zebrafish and vertebrate immunity | journal = Disease Models & Mechanisms | volume = 5 | issue = 1 | pages = 38–47 | date = January 2012 | pmid = 22228790 | pmc = 3255542 | doi = 10.1242/dmm.007138 }}</ref><ref>{{cite journal | vauthors = Meijer AH, Spaink HP | title = Host-pathogen interactions made transparent with the zebrafish model | journal = Current Drug Targets | volume = 12 | issue = 7 | pages = 1000–1017 | date = June 2011 | pmid = 21366518 | pmc = 3319919 | doi = 10.2174/138945011795677809 }}</ref><ref>{{cite journal | vauthors = van der Vaart M, Spaink HP, Meijer AH | title = Pathogen recognition and activation of the innate immune response in zebrafish | journal = Advances in Hematology | volume = 2012 | pages = 159807 | year = 2012 | pmid = 22811714 | pmc = 3395205 | doi = 10.1155/2012/159807 | doi-access = free }}</ref> The transparent early life stages are well suited for ''in vivo'' imaging and genetic dissection of host-pathogen interactions.<ref>{{cite journal | vauthors = Benard EL, van der Sar AM, Ellett F, Lieschke GJ, Spaink HP, Meijer AH | title = Infection of zebrafish embryos with intracellular bacterial pathogens | journal = Journal of Visualized Experiments | issue = 61 | date = March 2012 | pmid = 22453760 | pmc = 3415172 | doi = 10.3791/3781 }}</ref><ref>{{cite journal | vauthors = Meijer AH, van der Vaart M, Spaink HP | title = Real-time imaging and genetic dissection of host-microbe interactions in zebrafish | journal = Cellular Microbiology | volume = 16 | issue = 1 | pages = 39–49 | date = January 2014 | pmid = 24188444 | doi = 10.1111/cmi.12236 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Torraca V, Masud S, Spaink HP, Meijer AH | title = Macrophage-pathogen interactions in infectious diseases: new therapeutic insights from the zebrafish host model | journal = Disease Models & Mechanisms | volume = 7 | issue = 7 | pages = 785–797 | date = July 2014 | pmid = 24973749 | pmc = 4073269 | doi = 10.1242/dmm.015594 }}</ref><ref>{{cite journal | vauthors = Levraud JP, Palha N, Langevin C, Boudinot P | title = Through the looking glass: witnessing host-virus interplay in zebrafish | journal = Trends in Microbiology | volume = 22 | issue = 9 | pages = 490–497 | date = September 2014 | pmid = 24865811 | doi = 10.1016/j.tim.2014.04.014 }}</ref> Zebrafish models for a wide range of bacterial, viral and parasitic pathogens have already been established; for example, the zebrafish model for tuberculosis provides fundamental insights into the mechanisms of pathogenesis of mycobacteria.<ref>{{Cite book | vauthors = Ramakrishnan L | volume = 783 | pages = 251–66 | year = 2013 | pmid = 23468113 | doi = 10.1007/978-1-4614-6111-1_13 | isbn = 978-1-4614-6110-4 | series = Advances in Experimental Medicine and Biology | title = The New Paradigm of Immunity to Tuberculosis | chapter = Looking Within the Zebrafish to Understand the Tuberculous Granuloma }}</ref><ref>{{cite journal | vauthors = Ramakrishnan L | title = The zebrafish guide to tuberculosis immunity and treatment | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 78 | pages = 179–192 | year = 2013 | pmid = 24643219 | doi = 10.1101/sqb.2013.78.023283 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cronan MR, Tobin DM | title = Fit for consumption: zebrafish as a model for tuberculosis | journal = Disease Models & Mechanisms | volume = 7 | issue = 7 | pages = 777–784 | date = July 2014 | pmid = 24973748 | pmc = 4073268 | doi = 10.1242/dmm.016089 }}</ref><ref>{{cite journal | vauthors = Meijer AH | title = Protection and pathology in TB: learning from the zebrafish model | journal = Seminars in Immunopathology | volume = 38 | issue = 2 | pages = 261–273 | date = March 2016 | pmid = 26324465 | pmc = 4779130 | doi = 10.1007/s00281-015-0522-4 }}</ref> Furthermore, robotic technology has been developed for  high-throughput antimicrobial drug screening using zebrafish infection models.<ref>{{cite journal | vauthors = Spaink HP, Cui C, Wiweger MI, Jansen HJ, Veneman WJ, Marín-Juez R, de Sonneville J, Ordas A, Torraca V, van der Ent W, Leenders WP, Meijer AH, Snaar-Jagalska BE, Dirks RP | display-authors = 6 | title = Robotic injection of zebrafish embryos for high-throughput screening in disease models | journal = Methods | volume = 62 | issue = 3 | pages = 246–254 | date = August 2013 | pmid = 23769806 | doi = 10.1016/j.ymeth.2013.06.002 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Veneman WJ, Marín-Juez R, de Sonneville J, Ordas A, Jong-Raadsen S, Meijer AH, Spaink HP | title = Establishment and optimization of a high throughput setup to study Staphylococcus epidermidis and Mycobacterium marinum infection as a model for drug discovery | journal = Journal of Visualized Experiments | volume = 88 | issue = 88 | pages = e51649 | date = June 2014 | pmid = 24998295 | pmc = 4206090 | doi = 10.3791/51649 }}</ref>
 ===Repairing retinal damage===
@@ Line 205: / Line 205: @@
 Another notable characteristic of the zebrafish is that it possesses four types of [[cone cell]], with [[ultraviolet]]-sensitive cells supplementing the red, green and blue cone cell subtypes found in humans. Zebrafish can thus observe a very wide spectrum of colours. The species is also studied to better understand the development of the retina; in particular, how the cone cells of the retina become arranged into the so-called 'cone mosaic'. Zebrafish, in addition to certain other [[teleost]] fish, are particularly noted for having extreme precision of cone cell arrangement.<ref>{{cite journal | vauthors = Allison WT, Barthel LK, Skebo KM, Takechi M, Kawamura S, Raymond PA | title = Ontogeny of cone photoreceptor mosaics in zebrafish | journal = The Journal of Comparative Neurology | volume = 518 | issue = 20 | pages = 4182–4195 | date = October 2010 | pmid = 20878782 | pmc = 3376642 | doi = 10.1002/cne.22447 }}</ref>
-This study of the zebrafish's retinal characteristics has also extrapolated into medical enquiry. In 2007, researchers at [[University College London]] grew a type of zebrafish adult [[stem cell]] found in the eyes of fish and mammals that develops into [[neuron]]s in the retina. These could be injected into the eye to treat diseases that damage retinal neurons—nearly every disease of the eye, including [[macular degeneration]], [[glaucoma]], and [[diabetes]]-related blindness. The researchers studied Müller [[glial cells]] in the eyes of humans aged from 18 months to 91 years, and were able to develop them into all types of retinal neurons. They were also able to grow them easily in the lab. The stem cells successfully migrated into diseased rats' retinas, and took on the characteristics of the surrounding neurons. The team stated that they intended to develop the same approach in humans.<ref>{{cite journal | vauthors = Lawrence JM, Singhal S, Bhatia B, Keegan DJ, Reh TA, Luthert PJ, Khaw PT, Limb GA | title = MIO-M1 cells and similar muller glial cell lines derived from adult human retina exhibit neural stem cell characteristics | journal = Stem Cells | volume = 25 | issue = 8 | pages = 2033–2043 | date = August 2007 | pmid = 17525239 | doi = 10.1634/stemcells.2006-0724 | lay-url = http://www.chinapost.com.tw/health/eye%20health/2007/08/03/116860/Zebra-fish.htm | doi-access = free | lay-date = August 3, 2007 | lay-source = [[The China Post]] }}</ref>
+This study of the zebrafish's retinal characteristics has also extrapolated into medical enquiry. In 2007, researchers at [[University College London]] grew a type of zebrafish adult [[stem cell]] found in the eyes of fish and mammals that develops into [[neuron]]s in the retina. These could be injected into the eye to treat diseases that damage retinal neurons—nearly every disease of the eye, including [[macular degeneration]], [[glaucoma]], and [[diabetes]]-related blindness. The researchers studied Müller [[glial cells]] in the eyes of humans aged from 18 months to 91 years, and were able to develop them into all types of retinal neurons. They were also able to grow them easily in the lab. The stem cells successfully migrated into diseased rats' retinas, and took on the characteristics of the surrounding neurons. The team stated that they intended to develop the same approach in humans.<ref>{{cite journal | vauthors = Lawrence JM, Singhal S, Bhatia B, Keegan DJ, Reh TA, Luthert PJ, Khaw PT, Limb GA | display-authors = 6 | title = MIO-M1 cells and similar muller glial cell lines derived from adult human retina exhibit neural stem cell characteristics | journal = Stem Cells | volume = 25 | issue = 8 | pages = 2033–2043 | date = August 2007 | pmid = 17525239 | doi = 10.1634/stemcells.2006-0724 | lay-url = http://www.chinapost.com.tw/health/eye%20health/2007/08/03/116860/Zebra-fish.htm | doi-access = free | lay-date = August 3, 2007 | lay-source = [[The China Post]] }}</ref>
 === Muscular dystrophies ===
@@ Line 211: / Line 211: @@
 === Bone physiology and pathology ===
-Zebrafish have been used as model organisms for bone metabolism, tissue turnover, and resorbing activity. These processes are largely evolutionary conserved. They have been used to study osteogenesis (bone formation), evaluating differentiation, matrix deposition activity, and cross-talk of skeletal cells, to create and isolate mutants modeling human bone diseases, and test new chemical compounds for the ability to revert bone defects.<ref>{{cite journal | last1=Witten|first1=P. E.|last2=Hansen|first2=A.|last3=Hall|first3=B. K. | title = Features of mono- and multinucleated bone resorbing cells of the zebrafish Danio rerio and their contribution to skeletal development, remodeling, and growth | journal = Journal of Morphology | volume = 250 | issue = 3 | pages = 197–207 | date = December 2001 | pmid = 11746460 | doi = 10.1002/jmor.1065 | s2cid = 33403358 }}</ref><ref>{{cite journal | first1=Marta|last1=Carnovali|first2=Giuseppe|last2=Banfi | title = Zebrafish Models of Human Skeletal Disorders: Embryo and Adult Swimming Together | journal = BioMed Research International | volume = 2019 | pages = 1253710 | year = 2019 | pmid = 31828085 | pmc = 6886339 | doi = 10.1155/2019/1253710 | doi-access = free }}</ref> The larvae can be used to follow new (''de novo'') osteoblast formation during bone development. They start mineralising bone elements as early as 4 days post fertilisation. Recently, adult zebrafish are being used to study complex age related bone diseases such as [[osteoporosis]] and [[osteogenesis imperfecta]].<ref name=":1">{{cite journal | last1=Bergen|first1=Dylan J. M.|last2=Kague|first2=Erika|last3=Hammond|first3=Chrissy L. | title = Zebrafish as an Emerging Model for Osteoporosis: A Primary Testing Platform for Screening New Osteo-Active Compounds | journal = Frontiers in Endocrinology | volume = 10 | pages = 6 | date = 2019 | pmid = 30761080 | pmc = 6361756 | doi = 10.3389/fendo.2019.00006 | doi-access = free }}</ref> The (elasmoid) [[Fish scale#Elasmoid scales|scales]] of zebrafish function as a protective external layer and are little bony plates made by osteoblasts. These exoskeletal structures are formed by bone matrix depositing osteoblasts and are remodeled by osteoclasts. The scales also act as the main calcium storage of the fish. They can be cultured ex-vivo (kept alive outside of the organism) in a multi-well plate, which allows manipulation with drugs and even screening for new drugs that could change bone metabolism (between osteoblasts and osteoclasts).<ref name=":1" /><ref>{{cite journal | last1=de Vrieze|first1=E.|last2=van Kessel|first2=M. A. H. J.|last3=Peters|first3=H. M.|last4=Spanings|first4=F. A. T.|last5=Flik|first5=G.|last6=Metz|first6=J. R. | title = Prednisolone induces osteoporosis-like phenotype in regenerating zebrafish scales | journal = Osteoporosis International | volume = 25 | issue = 2 | pages = 567–578 | date = February 2014 | pmid = 23903952 | doi = 10.1007/s00198-013-2441-3 | s2cid = 21829206 }}</ref><ref>{{cite journal | last1=de Vrieze|first1=Erik|last2=Zethof|first2=Jan|last3=Schulte-Merker|first3=Stefan|last4=Flik|first4=Gert|last5=Metz|first5=Juriaan R. | title = Identification of novel osteogenic compounds by an ex-vivo sp7:luciferase zebrafish scale assay | journal = Bone | volume = 74 | pages = 106–113 | date = May 2015 | pmid = 25600250 | doi = 10.1016/j.bone.2015.01.006 }}</ref>
+Zebrafish have been used as model organisms for bone metabolism, tissue turnover, and resorbing activity. These processes are largely evolutionary conserved. They have been used to study osteogenesis (bone formation), evaluating differentiation, matrix deposition activity, and cross-talk of skeletal cells, to create and isolate mutants modeling human bone diseases, and test new chemical compounds for the ability to revert bone defects.<ref>{{cite journal | vauthors = Witten PE, Hansen A, Hall BK | title = Features of mono- and multinucleated bone resorbing cells of the zebrafish Danio rerio and their contribution to skeletal development, remodeling, and growth | journal = Journal of Morphology | volume = 250 | issue = 3 | pages = 197–207 | date = December 2001 | pmid = 11746460 | doi = 10.1002/jmor.1065 | s2cid = 33403358 }}</ref><ref>{{cite journal | vauthors = Carnovali M, Banfi G, Mariotti M | title = Zebrafish Models of Human Skeletal Disorders: Embryo and Adult Swimming Together | journal = BioMed Research International | volume = 2019 | pages = 1253710 | year = 2019 | pmid = 31828085 | pmc = 6886339 | doi = 10.1155/2019/1253710 | doi-access = free }}</ref> The larvae can be used to follow new (''de novo'') osteoblast formation during bone development. They start mineralising bone elements as early as 4 days post fertilisation. Recently, adult zebrafish are being used to study complex age related bone diseases such as [[osteoporosis]] and [[osteogenesis imperfecta]].<ref name=":1">{{cite journal | vauthors = Bergen DJ, Kague E, Hammond CL | title = Zebrafish as an Emerging Model for Osteoporosis: A Primary Testing Platform for Screening New Osteo-Active Compounds | journal = Frontiers in Endocrinology | volume = 10 | pages = 6 | date = 2019 | pmid = 30761080 | pmc = 6361756 | doi = 10.3389/fendo.2019.00006 | doi-access = free }}</ref> The (elasmoid) [[Fish scale#Elasmoid scales|scales]] of zebrafish function as a protective external layer and are little bony plates made by osteoblasts. These exoskeletal structures are formed by bone matrix depositing osteoblasts and are remodeled by osteoclasts. The scales also act as the main calcium storage of the fish. They can be cultured ex-vivo (kept alive outside of the organism) in a multi-well plate, which allows manipulation with drugs and even screening for new drugs that could change bone metabolism (between osteoblasts and osteoclasts).<ref name=":1" /><ref>{{cite journal | vauthors = de Vrieze E, van Kessel MA, Peters HM, Spanings FA, Flik G, Metz JR | title = Prednisolone induces osteoporosis-like phenotype in regenerating zebrafish scales | journal = Osteoporosis International | volume = 25 | issue = 2 | pages = 567–578 | date = February 2014 | pmid = 23903952 | doi = 10.1007/s00198-013-2441-3 | s2cid = 21829206 }}</ref><ref>{{cite journal | vauthors = de Vrieze E, Zethof J, Schulte-Merker S, Flik G, Metz JR | title = Identification of novel osteogenic compounds by an ex-vivo sp7:luciferase zebrafish scale assay | journal = Bone | volume = 74 | pages = 106–113 | date = May 2015 | pmid = 25600250 | doi = 10.1016/j.bone.2015.01.006 }}</ref>
 === Diabetes ===
@@ Line 223: / Line 223: @@
 === Epilepsy ===
-Zebrafish have been used as a model system to study epilepsy. Mammalian seizures can be recapitulated molecularly, behaviorally, and electrophysiologically, using a fraction of the resources required for experiments in mammals.<ref>{{cite journal | last1=Cho|first1=Sung-Joon|last2=Park|first2=Eugene|last3=Baker|first3=Andrew|last4=Reid|first4=Aylin Y. | title = Age Bias in Zebrafish Models of Epilepsy: What Can We Learn From Old Fish? | journal = Frontiers in Cell and Developmental Biology | volume = 8 | pages = 573303 | date = 2020-09-10 | pmid = 33015065 | pmc = 7511771 | doi = 10.3389/fcell.2020.573303 | doi-access = free }}</ref>
+Zebrafish have been used as a model system to study epilepsy. Mammalian seizures can be recapitulated molecularly, behaviorally, and electrophysiologically, using a fraction of the resources required for experiments in mammals.<ref>{{cite journal | vauthors = Cho SJ, Park E, Baker A, Reid AY | title = Age Bias in Zebrafish Models of Epilepsy: What Can We Learn From Old Fish? | journal = Frontiers in Cell and Developmental Biology | volume = 8 | pages = 573303 | date = 2020-09-10 | pmid = 33015065 | pmc = 7511771 | doi = 10.3389/fcell.2020.573303 | doi-access = free }}</ref>
 == See also ==
@@ Line 235: / Line 235: @@
 == Further reading ==
 {{refbegin|32em}}
-* {{cite book | last = Lambert | first = Derek J | name-list-style = vanc | title = Freshwater Aquarium Fish | location = Edison, New Jersey | publisher = Chartwell Books | year = 1997 | page = 19 | isbn = 978-0-7858-0867-1 | url-access = registration | url = https://archive.org/details/freshwateraquari00dere/page/19 }}
+* {{cite book | last = Lambert | first = Derek J | name-list-style = vanc | title = Freshwater Aquarium Fish | location = Edison, New Jersey | publisher = Chartwell Books | year = 1997 | page = [https://archive.org/details/freshwateraquari00dere/page/19 19] | isbn = 978-0-7858-0867-1 | url-access = registration | url = https://archive.org/details/freshwateraquari00dere/page/19 }}
 * {{cite web | last = Sharpe | first = Shirlie | name-list-style = vanc |title=Zebra Danio|website=Your Guide to Freshwater Aquariums|url=http://freshaquarium.about.com/cs/cyprinids2/p/zebradanio.htm|access-date=December 15, 2004}}
-* {{cite journal | vauthors = Kocher TD, Jeffery WR, Parichy DM, Peichel CL, Streelman JT, Thorgaard GH | title = Special feature{{mdash}}roundtable discussion - Fish models for studying adaptive evolution and speciation | journal = Zebrafish | volume = 2 | issue = 3 | pages = 147–156 | year = 2005 | pmid = 18248189 | doi = 10.1089/zeb.2005.2.147 | s2cid = 18940475 }}
+* {{cite journal | vauthors = Kocher TD, Jeffery WR, Parichy DM, Peichel CL, Streelman JT, Thorgaard GH | title = Special feature--roundtable discussion. Fish models for studying adaptive evolution and speciation | journal = Zebrafish | volume = 2 | issue = 3 | pages = 147–156 | year = 2005 | pmid = 18248189 | doi = 10.1089/zeb.2005.2.147 | s2cid = 18940475 }}
 * {{cite journal | vauthors = Bradbury J | title = Small fish, big science | journal = PLOS Biology | volume = 2 | issue = 5 | pages = E148 | date = May 2004 | pmid = 15138510 | pmc = 406403 | doi = 10.1371/journal.pbio.0020148 }}
-* {{cite book | vauthors = Westerfield M |year=2007 |title=The zebrafish book: A guide for the laboratory use of zebrafish ''Danio* (Brachydanio) rerio'' |edition=5th |publisher=University of Oregon Press |location=Eugene, OR | asin=B003KFCWKS}}
+* {{cite book | vauthors = Westerfield M |year=2007 |title=The zebrafish book. A guide for the laboratory use of zebrafish (''Danio rerio'') |edition=5th |publisher=University of Oregon Press |location=Eugene, OR}}
 * {{cite journal |doi=10.1038/nature.2012.11463 |title=Targeted gene modification can rewrite zebrafish DNA |year=2012 |last1=Guttridge |first1=Nicky | name-list-style = vanc |journal=Nature|s2cid=87708919 }}
 * {{Cite news|url=https://www.bbc.co.uk/news/magazine-22904931|title=A Point Of View: Fly, Fish, Mouse and Worm|publisher=BBC|date=June 14, 2013|access-date=June 15, 2013|newspaper=BBC News}}

Taxon identifiers
Danio rerio	Wikidata: Q169444 Wikispecies: Danio rerio ADW: Danio_rerio BOLD: 19573 CoL: 3443J EoL: 204011 EPPO: BRCDRE FishBase: 4653 GBIF: 9797255 iNaturalist: 49977 IRMNG: 11303984 ITIS: 163699 IUCN: 166487 NAS: 505 NCBI: 7955 Open Tree of Life: 1005914 WoRMS: 1026595
Cyprinus rerio	Wikidata: Q106388306 CoL: 33HY8 GBIF: 2362686 IRMNG: 10160075 ITIS: 163669 WoRMS: 1013626 ZooBank: 4B89B955-01FC-4610-8399-F1C2559E94DB