In brief Apart from mice, meiosis initiation factors and their transcriptional regulation mechanisms are largely unknown in mammals. This study suggests that STRA8 and MEIOSIN are both meiosis initiation factors in mammals, but their... more
In brief Apart from mice, meiosis initiation factors and their transcriptional regulation mechanisms are largely unknown in mammals. This study suggests that STRA8 and MEIOSIN are both meiosis initiation factors in mammals, but their transcription is epigenetically regulated differently from each other. In the mouse, the timing of meiosis onset differs between sexes due to the sex-specific regulation of the meiosis initiation factors, STRA8 and MEIOSIN. Before the initiation of meiotic prophase I, the Stra8 promoter loses suppressive histone-3-lysine-27 trimethylation (H3K27me3) in both sexes, suggesting that H3K27me3-associated chromatin remodelling may be responsible for activating STRA8 and its co-factor MEIOSIN. Here we examined MEIOSIN and STRA8 expression in a eutherian (the mouse), two marsupials (the grey short-tailed opossum and the tammar wallaby) and two monotremes (the platypus and the short-beaked echidna) to ask whether this pathway is conserved between all mammals. The conserved expression of both genes in all three mammalian groups and of MEIOSIN and STRA8 protein in therian mammals suggests that they are the meiosis initiation factors in all mammals. Analyses of published DNase-seq and chromatin-immunoprecipitation sequencing (ChIP-seq) data sets confirmed that H3K27me3-associated chromatin remodelling occurred at the STRA8, but not the MEIOSIN, promoter in therian mammals. Furthermore, culturing tammar ovaries with an inhibitor of H3K27me3 demethylation before meiotic prophase I affected STRA8 but not MEIOSIN transcriptional levels. Our data suggest that H3K27me3-associated chromatin remodelling is an ancestral mechanism that allows STRA8 expression in mammalian pre-meiotic germ cells.
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In the short-beaked echidna, Tachyglossus aculeatus, after an initial period of in utero development, the egg is laid in the pouch and incubated for 10 days. During this time, fetuses develop an egg tooth and caruncle to help them hatch.... more
In the short-beaked echidna, Tachyglossus aculeatus, after an initial period of in utero development, the egg is laid in the pouch and incubated for 10 days. During this time, fetuses develop an egg tooth and caruncle to help them hatch. However, there are only a few historical references that describe the development of the monotreme egg tooth. Using unprecedented access to echidna pre- and post-hatching tissues, the egg tooth and caruncle were assessed by micro-CT, histology and immunofluorescence, to map the changes at the morphological and molecular level. Unlike mammalian tooth germs that develop by invagination of a placode, the echidna egg tooth developed by evagination, similar to that of the first teeth in some reptiles. The egg tooth ankylosed to the premaxilla, rather than forming a mammalian thecodont attachment, with loss of the egg tooth post-hatching associated with high levels of odontoclasts, and apoptosis. The caruncle formed as a separate mineralisation from the a...
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Mammals articulate their jaws using a novel joint between the dentary and squamosal bones. In eutherian mammals, this joint forms in the embryo, supporting feeding and vocalisation from birth. In contrast, marsupials and monotremes... more
Mammals articulate their jaws using a novel joint between the dentary and squamosal bones. In eutherian mammals, this joint forms in the embryo, supporting feeding and vocalisation from birth. In contrast, marsupials and monotremes exhibit extreme altriciality and are born before the bones of the novel mammalian jaw joint form. These mammals need to rely on other mechanisms to allow them to feed. Here, we show that this vital function is carried out by the earlier developing, cartilaginous incus of the middle ear, abutting the cranial base to form a cranio-mandibular articulation. The nature of this articulation varies between monotremes and marsupials, with juvenile monotremes retaining a double articulation, similar to that of the fossil mammaliaform Morganucodon, while marsupials use a versican-rich matrix to stabilise the jaw against the cranial base. These findings provide novel insight into the evolution of mammals and the changing relationship between the jaw and ear.
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Embryonic diapause is a period of developmental arrest which requires coordination of a molecular cross-talk between the endometrium and blastocyst to ensure a successful reactivation, but the exact mechanisms are undefined. The... more
Embryonic diapause is a period of developmental arrest which requires coordination of a molecular cross-talk between the endometrium and blastocyst to ensure a successful reactivation, but the exact mechanisms are undefined. The objectives of this study were to screen the tammar blastocyst for potential diapause control factors and to investigate the potential for members of the epidermal growth factor (EGF) family to coordinate reactivation. A select number of factors were also examined in the mink to determine whether their expression patterns were conserved across diapause species. The full-length sequences of the tammar genes of interest were first cloned to establish their level of sequence conservation with other mammals. The uterine expression of EGF family members EGF and heparin-binding EGF (HBEGF) and their receptors (EGFR and erb-b2 receptor tyrosine kinase 4 (ERBB4)) was determined by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohistoch...
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Embryonic diapause is an evolutionary strategy to ensure that offspring are born when maternal and environmental conditions are optimal for survival. In many species of carnivores, obligate embryonic diapause occurs in every gestation.... more
Embryonic diapause is an evolutionary strategy to ensure that offspring are born when maternal and environmental conditions are optimal for survival. In many species of carnivores, obligate embryonic diapause occurs in every gestation. Reciprocal embryo transplant studies indicate that embryo arrest during diapause is conferred by uterine conditions and is due to a lack of specific factors necessary for continued development. In previous studies, global gene expression analysis revealed reduced uterine expression during diapause of a cluster of genes in the mink that regulate the abundance of polyamines, including ornithine decarboxylase 1 (ODC1). In addition, in vivo inhibition of the conversion of ornithine to the polyamine, putrescine, induced a reversible arrest in mink embryonic development and an arrest in trophoblast cell proliferation in vitro. Previous studies have implicated prolactin as the principal endocrine signal to terminate diapause. In this study, uterine expressio...
Research Interests: Biology, Medicine, Cell Division, Biological Sciences, Pregnancy, and 14 moreProlactin, Female, Animals, Phosphorylation, Diapause, Embryonic Development, Epithelial cells, Putrescine, Mink, Cell Proliferation, Uterus, Gene Expression Regulation, Biology Reproduction, and Medical and Health Sciences
The imprinted isoform of the Mestgene in mice is involved in key mammalian traits such as placental and fetal growth, maternal care and mammary gland maturation. MEST has a distinct promoter differentially methylated region (DMR) in... more
The imprinted isoform of the Mestgene in mice is involved in key mammalian traits such as placental and fetal growth, maternal care and mammary gland maturation. MEST has a distinct promoter differentially methylated region (DMR) in eutherian mammals but in marsupials, while MEST was thought to be imprinted, it had no DMR. In this study, we examined similarities and differences in the MEST gene locus across mammals using a marsupial, the tammar wallaby, a monotreme, the platypus, and a eutherian, the mouse, to investigate how MEST imprinting evolved in mammals. By confirming the presence of the short isoform in all mammalian groups (which is imprinted in eutherians), this study suggests that an alternative promoter for the short isoform has evolved at the MESTgene locus in the common ancestor of mammals. In the tammar, the short isoform of MEST shared the putative promoter CpG island with an antisense lncRNA previously identified in humans and an isoform of a neighbouring gene CEP41...
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Genomic imprinting is found in marsupial and eutherian mammals, but not in monotremes. While the primary regulator of genomic imprinting in eutherians is differential DNA methylation between parental alleles, conserved imprinted genes in... more
Genomic imprinting is found in marsupial and eutherian mammals, but not in monotremes. While the primary regulator of genomic imprinting in eutherians is differential DNA methylation between parental alleles, conserved imprinted genes in marsupials tend to lack DNA methylation at their promoters. DNA methylation at eutherian imprinted genes is mainly catalyzed by a DNA methyltransferase (DNMT) enzyme, DNMT3A. There are two isoforms of eutherian DNMT3A: DNMT3A and DNMT3A2. DNMT3A2 is the primary isoform for establishing DNA methylation at eutherian imprinted genes and is essential for eutherian genomic imprinting. In this study, we investigated whether DNMT3A2 is also present in the two other mammalian lineages, marsupials and monotremes. We identified DNMT3A2 in both marsupials and monotremes, although imprinting has not been identified in monotremes. By analyzing genomic sequences and transcriptome data across vertebrates, we concluded that the evolution of DNMT3A2 occurred in the ...
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The reproduction of the mink, Neovison vison, has been extensively studied over the past 70 years. The endocrine control of pregnancy is reasonably well understood, but our understanding of early embryo development is limited. The mink is... more
The reproduction of the mink, Neovison vison, has been extensively studied over the past 70 years. The endocrine control of pregnancy is reasonably well understood, but our understanding of early embryo development is limited. The mink is one of the best characterized mammals for the study of embryonic diapause, but in order to unravel the complex interactions that occur between the blastocyst and the uterus during diapause and reactivation, a defined culture media system that supports growth is essential. Until recently, culture of the mink blastocyst has been relatively unsuccessful. This chapter will describe a method for successfully obtaining and culturing mink blastocysts and will highlight some of the unique challenges in working with this species. Methods to age match prediapause embryos in a mammal that exhibits superfetation, and to synchronize collection of reactivation from diapause stages using prolactin will be discussed. Finally, a quantitative method to determine the extent of cell proliferation in the blastocyst, a hallmark of reactivation from diapause, will be detailed.
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Monotremes diverged from therian mammal ancestors approximately 184 million years ago and have a number of novel reproductive characteristics. One in particular is their penile morphology. There are differences between echidna and... more
Monotremes diverged from therian mammal ancestors approximately 184 million years ago and have a number of novel reproductive characteristics. One in particular is their penile morphology. There are differences between echidna and platypus phalluses, but both are somewhat similar in structure to the reptilian phallus. The echidna penis consists of 4 rosette glans, each of which contains a termination of the quadrifurcate urethra, but it appears that only 2 of the 4 glans become erect at any one time. Despite this, only a few historical references describe the structure of the echidna penis and none provides an explanation for the mechanisms of unilateral ejaculation. This study confirmed that the echidna penis contains many of the same overall structures and morphology as other mammalian penises and a number of features homologous with reptiles. The corpus cavernosum is well supplied with blood, extends up to the base of the glans penis and is primarily responsible for erection. How...
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Egg-laying mammals (monotremes) are the only extant mammalian outgroup to therians (marsupial and eutherian animals) and provide key insights into mammalian evolution1,2. Here we generate and analyse reference genomes of the platypus... more
Egg-laying mammals (monotremes) are the only extant mammalian outgroup to therians (marsupial and eutherian animals) and provide key insights into mammalian evolution1,2. Here we generate and analyse reference genomes of the platypus (Ornithorhynchus anatinus) and echidna (Tachyglossus aculeatus), which represent the only two extant monotreme lineages. The nearly complete platypus genome assembly has anchored almost the entire genome onto chromosomes, markedly improving the genome continuity and gene annotation. Together with our echidna sequence, the genomes of the two species allow us to detect the ancestral and lineage-specific genomic changes that shape both monotreme and mammalian evolution. We provide evidence that the monotreme sex chromosome complex originated from an ancestral chromosome ring configuration. The formation of such a unique chromosome complex may have been facilitated by the unusually extensive interactions between the multi-X and multi-Y chromosomes that are ...
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This study describes the progesterone profile during pregnancy in sexually mature female captive short-beaked echidnas (Tachyglossus aculeatus aculeatus). Echidnas were monitored daily by video surveillance to confirm key reproductive... more
This study describes the progesterone profile during pregnancy in sexually mature female captive short-beaked echidnas (Tachyglossus aculeatus aculeatus). Echidnas were monitored daily by video surveillance to confirm key reproductive behaviour. Plasma samples were collected and pouch morphology was assessed three times a week. The pouch of the female echidna only develops during gestation and it was possible to create a four-stage grading system using the most distinguishable characteristics of pouch development. Maximum pouch development was associated with declining progesterone concentrations, with the pouch closing in a drawstring-like manner at oviposition. Control of pouch development in pregnant echidnas is not yet clear but later pouch development is associated with a decrease in progesterone and pouch closure and may be under mechanical influences of the egg or young in the pouch. The length of pregnancy was 16.7 ± 0.2 days with a 15.1 ± 1.0 days luteal phase followed by a...
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Mammals articulate their jaws using a novel joint between the dentary and squamosal bones. In eutherian mammals, this joint forms in the embryo, supporting feeding and vocalisation from birth. In contrast, marsupials and monotremes... more
Mammals articulate their jaws using a novel joint between the dentary and squamosal bones. In eutherian mammals, this joint forms in the embryo, supporting feeding and vocalisation from birth. In contrast, marsupials and monotremes exhibit extreme altriciality and are born before the bones of the novel mammalian jaw joint form. These mammals need to rely on other mechanisms to allow them to feed. Here we show that this vital function is carried out by the earlier developing, cartilaginous incus of the middle ear, abutting the cranial base to form a cranio-mandibular articulation. The nature of this articulation varies between monotremes and marsupials, with monotremes retaining a double articulation, similar to that described in the fossil mammaliaform,Morganucodon, while marsupials use a versican rich matrix to stabilise the jaw against the cranial base. These findings provide novel insight into the evolution of mammals and the relationship between the jaw and ear.
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SummaryRecovery from decreased cell volume is accomplished by a regulated increase of intracellular osmolarity. The acute response is activation of inorganic ion transport into the cell, the main effector of which is the Na+/H+ exchanger... more
SummaryRecovery from decreased cell volume is accomplished by a regulated increase of intracellular osmolarity. The acute response is activation of inorganic ion transport into the cell, the main effector of which is the Na+/H+ exchanger NHE1. NHE1 is rapidly activated by a cell volume decrease in early embryos, but how this occurs is incompletely understood. Elucidating cell volume-regulatory mechanisms in early embryos is important, as it has been shown that their dysregulation results in preimplantation developmental arrest. The kinase JAK2 has a role in volume-mediated NHE1 activation in at least some cells, including 2-cell stage mouse embryos. However, while 2-cell embryos show partial inhibition of NHE1 when JAK2 activity is blocked, NHE1 activation in 1-cell embryos is JAK2-independent, implying a requirement for additional signalling mechanisms. As focal adhesion kinase (FAK aka PTK2) becomes phosphorylated and activated in some cell types in response to decreased cell volu...
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Implantation is essential for the establishment of a successful pregnancy, and the preimplantation period plays a significant role in ensuring implantation occurs in a timely and coordinated manner. This requires effective... more
Implantation is essential for the establishment of a successful pregnancy, and the preimplantation period plays a significant role in ensuring implantation occurs in a timely and coordinated manner. This requires effective maternal-embryonic signalling, established during the preimplantation period, to synchronise development. Although multiple factors have been identified as present during this time, the exact molecular mechanisms involved are unknown. Polyamines are small cationic molecules that are ubiquitously expressed from prokaryotes to eukaryotes. Despite being first identified over 300 years ago, their essential roles in cell proliferation and growth, including cancer, have only been recently recognised, with new technologies and interest resulting in rapid expansion of the polyamine field. This review provides a summary of our current understanding of polyamine synthesis, regulation and function with a focus on recent developments demonstrating the requirements for polyami...
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Embryonic diapause – a period of embryonic suspension at the blastocyst stage – is a fascinating phenomenon that occurs in over 130 species of mammals, ranging from bears and badgers to mice and marsupials. It might even occur in humans.... more
Embryonic diapause – a period of embryonic suspension at the blastocyst stage – is a fascinating phenomenon that occurs in over 130 species of mammals, ranging from bears and badgers to mice and marsupials. It might even occur in humans. During diapause, there is minimal cell division and greatly reduced metabolism, and development is put on hold. Yet there are no ill effects for the pregnancy when it eventually continues. Multiple factors can induce diapause, including seasonal supplies of food, temperature, photoperiod and lactation. The successful reactivation and continuation of pregnancy then requires a viable embryo, a receptive uterus and effective molecular communication between the two. But how do the blastocysts survive and remain viable during this period of time, which can be up to a year in some cases? And what are the signals that bring it out of suspended animation? Here, we provide an overview of the process of diapause and address these questions, focussing on recen...
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Research Interests: Biology, Medicine, Embryo, Biological Sciences, Mice, and 15 moreFemale, Animals, Embryonic Stem Cell, Blastocyst, Diapause, Embryonic Development, Eflornithine, Oxford university, Endometrium, Gene Expression Regulation, Biology Reproduction, Conceptus, Ornithine decarboxylase, embryo implantation, and Medical and Health Sciences
ContentsEmbryonic diapause is an evolutionary strategy to ensure that offspring are born when maternal and environmental conditions are optimal for survival. In many species of carnivores, obligate embryonic diapause occurs in every... more
ContentsEmbryonic diapause is an evolutionary strategy to ensure that offspring are born when maternal and environmental conditions are optimal for survival. In many species of carnivores, obligate embryonic diapause occurs in every gestation. In mustelids, the regulation of diapause and reactivation is influenced by photoperiod, which then acts to regulate the secretion of pituitary prolactin. Prolactin in turn regulates ovarian steroid function. Reciprocal embryo transplant studies indicate that this state of embryonic arrest is conferred by uterine conditions and is presumed to be due to a lack of specific factors necessary for continued development. Studies of global gene expression in the mink (Neovison vison) revealed reduced expression of a cluster of genes that regulate the abundance of polyamines in the uterus during diapause, including the rate‐limiting enzyme in polyamine production, ornithine decarboxylase (ODC). In addition, in this species, in vivo inhibition of the co...
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In the tammar wallaby, Macropus eugenii, the blastocyst normally remains in embryonic diapause for 11 months without cell division or apoptosis occurring. Progesterone regulates reactivation by inducing active secretion from the... more
In the tammar wallaby, Macropus eugenii, the blastocyst normally remains in embryonic diapause for 11 months without cell division or apoptosis occurring. Progesterone regulates reactivation by inducing active secretion from the endometrium, but the molecular cross-talk between the endometrium and blastocyst is unknown. This process may involve the phospholipid paf. Paf is an embryotrophin that acts as a trophic/survival factor in the early embryo, partly by inactivating (via the PI3K/Akt pathway) the expression of p53, a cell cycle arrest factor (1,2). In vitro, paf production from the tammar endometrium increases after diapause (3). This study examined the expression of the paf receptor (pafr) and p53 in the tammar endometrium and embryo at entry into, during and reactivation from diapause. Both pafr and p53 mRNA were expressed in the endometrium at all stages. However there was no quantitative change in pafr expression. In the endometrium, pafr protein is present on the membrane ...
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Embryonic diapause is widespread amongst mammals, but is especially common in the kangaroos and wallabies. In the tammar, Macropus eugenii, the sequence of endocrine events leading to embryonic diapause and reactivation are well defined... more
Embryonic diapause is widespread amongst mammals, but is especially common in the kangaroos and wallabies. In the tammar, Macropus eugenii, the sequence of endocrine events leading to embryonic diapause and reactivation are well defined and the blastocyst can remain in diapause for up to 11 months without cell division or apoptosis occurring (Renfree and Shaw 2000). The ovarian hormones exert their effects on the blastocyst by alterations in the endometrial secretions, but the molecular cross-talk between the endometrium and blastocyst is unknown. One possible regulator of diapause is the phospholipid PAF, an embryotrophin that acts as a trophic/survival factor for the early embryo (O'Neill 2005) partly by inactivating the expression of p53, a cell cycle inhibitor, via the PI3-K pathway. PAF is released from the tammar endometrium around the time of reactivation from diapause (Kojima et al. 1993). This study examined the expression of PAF-R and p53 in the tammar endometrium at e...
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Embryonic diapause, a suspension of cell division and growth at the blastocyst stage, is widespread amongst mammals, but is especially common in the kangaroos and wallabies. In the tammar, Macropus eugenii, the sequence of endocrine... more
Embryonic diapause, a suspension of cell division and growth at the blastocyst stage, is widespread amongst mammals, but is especially common in the kangaroos and wallabies. In the tammar, Macropus eugenii, the sequence of endocrine events leading to embryonic diapause and reactivation are well defined[1]. The blastocyst can remain in diapause for up to 11 months without cell division, measurable metabolism or apoptosis occurring [2]. The ovarian hormones, especially progesterone, exert their effects on the blastocyst by alterations in the endometrial secretions [3], but the molecular cross-talk between the endometrium and blastocyst is unknown. There is increasing evidence for the involvement of leukaemia inhibitory factor (LIF)but the epidermal growth factor (EGF) family of growth factors are also likely to be involved.This study examined the expression of EGF and HB-EGF as well as their receptors, ERBB1 and ERBB4, in the tammar endometrium and blastocyst at entry into, and reacti...
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The control of reactivation from embryonic diapause in the tammar wallaby (Macropus eugenii) involves sequential activation of the corpus luteum, secretion of progesterone that stimulates endometrial secretion and subsequent changes in... more
The control of reactivation from embryonic diapause in the tammar wallaby (Macropus eugenii) involves sequential activation of the corpus luteum, secretion of progesterone that stimulates endometrial secretion and subsequent changes in the uterine environment that activate the embryo. However, the precise signals between the endometrium and the blastocyst are currently unknown. In eutherians, both the phospholipid Paf and its receptor, platelet-activating factor receptor (PTAFR), are present in the embryo and the endometrium. In the tammar, endometrial Paf releasein vitroincreases around the time of the early progesterone pulse that occurs around the time of reactivation, but whether Paf can reactivate the blastocyst is unknown. We cloned and characterised the expression of PTAFR in the tammar embryo and endometrium at entry into embryonic diapause, during its maintenance and after reactivation. Tammar PTAFR sequence and protein were highly conserved with mammalian orthologues. In t...
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Research Interests: Endocrinology, Developmental Biology, Biology, Morphogenesis, Medicine, and 15 moreBiological Sciences, Internal Medicine, Female, Animals, Male, Androgens, Prostate, tESTIS, Macropodidae, Sex Differentiation, Androgen, Epididymis, Sexual Differentiation, Mesonephric duct, and Medical and Health Sciences
Background The thymus plays a critical role in the development and maturation of T-cells. Humans have a single thoracic thymus and presence of a second thymus is considered an anomaly. However, many vertebrates have multiple thymuses. The... more
Background The thymus plays a critical role in the development and maturation of T-cells. Humans have a single thoracic thymus and presence of a second thymus is considered an anomaly. However, many vertebrates have multiple thymuses. The tammar wallaby has two thymuses: a thoracic thymus (typically found in all mammals) and a dominant cervical thymus. Researchers have known about the presence of the two wallaby thymuses since the 1800s, but no genome-wide research has been carried out into possible functional differences between the two thymic tissues. Here, we used pyrosequencing to compare the transcriptomes of a cervical and thoracic thymus from a single 178 day old tammar wallaby. Results We show that both the tammar thoracic and the cervical thymuses displayed gene expression profiles consistent with roles in T-cell development. Both thymuses expressed genes that mediate distinct phases of T-cells differentiation, including the initial commitment of blood stem cells to the T-l...