Down syndrome (DS) results from trisomy of human chromosome 21 (Hsa21) and is associated with an increased risk of Alzheimer’sdisease (AD). Here, using the unique transchromosomic Tc1 mouse model of DS we investigate the influence of... more
Down syndrome (DS) results from trisomy of human chromosome 21 (Hsa21) and is associated with an increased risk of Alzheimer’sdisease (AD). Here, using the unique transchromosomic Tc1 mouse model of DS we investigate the influence of trisomy of Hsa21 on the protein tau, which is hyperphosphorylated in Alzheimer’s disease. We show that in old, but not young, Tc1 mice increased phosphorylation of tau occurs at a site suggested to be targeted by the Hsa21 encoded kinase, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase
1A (DYRK1A). We show that DYRK1A is upregulated in young and old Tc1 mice, but that young trisomic mice may be protected from
accumulating aberrantly phosphorylated tau. We observe that the key tau kinase, glycogen synthase kinase3- (GSK-3) is aberrantly
phosphorylated at an inhibitory site in the aged Tc1 brain which may reduce total glycogen synthase kinase3- activity. It is possible that a similar mechanism may also occur in people with DS.
Cardiac malformations are prevalent in trisomies of human chromosome 21... more
Cardiac malformations are prevalent in trisomies of human chromosome 21 [Down's syndrome (DS)], affecting normal chamber separation in the developing heart. Efforts to understand the aetiology of these defects have been severely hampered by the absence of an accurate mouse model. Such models have proved challenging to establish because synteny with human chromosome Hsa21 is distributed across three mouse chromosomes. None of those engineered so far accurately models the full range of DS cardiac phenotypes, in particular the profound disruptions resulting from atrioventricular septal defects (AVSDs). Here, we present analysis of the cardiac malformations exhibited by embryos of the transchromosomic mouse line Tc(Hsa21)1TybEmcf (Tc1) which contains more than 90% of chromosome Hsa21 in addition to the normal diploid mouse genome. Using high-resolution episcopic microscopy and three-dimensional (3D) modelling, we show that Tc1 embryos exhibit many of the cardiac defects found in DS, including balanced AVSD with single and separate valvar orifices, membranous and muscular ventricular septal defects along with outflow tract and valve leaflet abnormalities. Frequencies of cardiac malformations (ranging from 38 to 55%) are dependent on strain background. In contrast, no comparable cardiac defects were detected in embryos of the more limited mouse trisomy model, Dp(16Cbr1-ORF9)1Rhr (Ts1Rhr), indicating that trisomy of the region syntenic to the Down's syndrome critical region, including the candidate genes DSCAM and DYRK1A, is insufficient to yield DS cardiac abnormalities. The Tc1 mouse line provides a suitable model for studying the underlying genetic causes of the DS AVSD cardiac phenotype.
Down Syndrome (DS) is a highly prevalent developmental disorder, affecting 1/700 births. Intellectual disability, which affects learning and memory, is present in all cases and is reflected by below average IQ. We sought to determine... more
Down Syndrome (DS) is a highly prevalent developmental disorder, affecting 1/700 births. Intellectual disability, which affects learning and memory, is present in all cases and is reflected by below average IQ. We sought to determine whether defective morphology and connectivity in neurons of the cerebral cortex may underlie the cognitive deficits that have been described in two mouse models of DS, the Tc1 and Ts1Rhr mouse lines. We utilised in utero electroporation to label a cohort of future upper layer projection neurons in the cerebral cortex of developing mouse embryos with GFP, and then examined neuronal positioning and morphology in early adulthood, which revealed no alterations in cortical layer position or morphology in either Tc1 or Ts1Rhr mouse cortex. The number of dendrites, as well as dendrite length and branching was normal in both DS models, compared with wildtype controls. The sites of projection neuron synaptic inputs, dendritic spines, were analysed in Tc1 and Ts1Rhr cortex at three weeks and three months after birth, and significant changes in spine morphology were observed in both mouse lines. Ts1Rhr mice had significantly fewer thin spines at three weeks of age. At three months of age Tc1 mice had significantly fewer mushroom spines--the morphology associated with established synaptic inputs and learning and memory. The decrease in mushroom spines was accompanied by a significant increase in the number of stubby spines. This data suggests that dendritic spine abnormalities may be a more important contributor to cognitive deficits in DS models, rather than overall neuronal architecture defects.
Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is the most common cause of congenital heart defects (CHD), yet the genetic and mechanistic causes of these defects remain unknown. To identify dosage-sensitive genes... more
Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is the most common cause of congenital heart defects (CHD), yet the genetic and mechanistic causes of these defects remain unknown. To identify dosage-sensitive genes that cause DS phenotypes, including CHD, we used chromosome engineering to generate a mapping panel of 7 mouse strains with partial trisomies of regions of mouse chromosome 16 orthologous to Hsa21. Using high-resolution episcopic microscopy and three-dimensional modeling we show that these strains accurately model DS CHD. Systematic analysis of the 7 strains identified a minimal critical region sufficient to cause CHD when present in 3 copies, and showed that it contained at least two dosage-sensitive loci. Furthermore, these new strains model a specific subtype of atrio-ventricular septal defects with exclusive ventricular shunting and demonstrate that, contrary to current hypotheses, these CHD are not due to failure in formation of the dorsal mesen...
Divergence is the first phase of speciation and is commonly thought to occur more readily in allopatric populations. Subspecies are populations that are divergent but generally retain the capacity to interbreed should they come into... more
Divergence is the first phase of speciation and is commonly thought to occur more readily in allopatric populations. Subspecies are populations that are divergent but generally retain the capacity to interbreed should they come into contact. Two subspecies of the Thick-billed Grasswren (Amytornis modestus) are divergent by 1.7% at the mitochondrial ND2 gene and were previously considered to be allopatric. In this study, we discovered that the subspecies were parapatric. We use a larger sample size than previous studies to examine variation in morphology and mitochondrial haplotype across the distribution of each subspecies and within the region of parapatry. The subspecies occurring to the west, Amytornis modestus indulkanna, had larger body size and longer and narrower bill than the subspecies occurring to the east, A. m. raglessi. Within the region of parapatry, females were morphologically similar to A. m. indulkanna but had eastern mitochondrial haplotypes while males had intermediate morphology and either eastern or western haplotypes. Additionally, haplotypes from the western mitochondrial clade were found in A. m. raglessi. These patterns of morphology and mitochondrial diversity reveal discordance within the region of parapatry and to the east. We suggest that the subspecies have undergone asymmetric expansion from west to east, made secondary contact, and are currently hybridising.
Information on the extent of genetic differentiation among seabird populations is essential for conservation planning. Here we used, for the first time in little penguins (Eudyptula minor), a next generation sequencing approach to... more
Information on the extent of genetic differentiation among seabird populations is essential for conservation planning. Here we used, for the first time in little penguins (Eudyptula minor), a next generation sequencing approach to investigate population genetic structure, gene flow and inbreeding among eight colonies in South Australia. We found that Troubridge Island individuals were genetically distinct from the other sampled colonies, and that colonies on all islands were connected by moderate levels of gene flow possibly due to migration from the Kangaroo Island colonies. While further genetic sampling is needed, these data support the idea that South Australia may be a zone of subtle and rapid genetic change for little penguins.
Trisomy of human chromosome 21 (Hsa21) results in Down syndrome (DS), a disorder that affects many aspects of physiology, including hematopoiesis. DS children have greatly increased rates of acute lymphoblastic leukemia and acute... more
Trisomy of human chromosome 21 (Hsa21) results in Down syndrome (DS), a disorder that affects many aspects of physiology, including hematopoiesis. DS children have greatly increased rates of acute lymphoblastic leukemia and acute megakaryoblastic leukemia (AMKL); DS newborns present with transient myeloproliferative disorder (TMD), a preleukemic form of AMKL. TMD and DS-AMKL almost always carry an acquired mutation in GATA1 resulting in exclusive synthesis of a truncated protein (GATA1s), suggesting that both trisomy 21 and GATA1 mutations are required for leukemogenesis. To gain further understanding of how Hsa21 contributes to hematopoietic abnormalities, we examined the Tc1 mouse model of DS, which carries an almost complete freely segregating copy of Hsa21, and is the most complete model of DS available. We show that although Tc1 mice do not develop leukemia, they have macrocytic anemia and increased extramedullary hematopoiesis. Introduction of GATA1s into Tc1 mice resulted in ...
Scabies, a parasitic skin infestation by the burrowing “itch” mite Sarcoptes scabiei , causes significant health problems for children and adults worldwide. Crusted scabies is a particularly severe form of scabies in which mites multiply... more
Scabies, a parasitic skin infestation by the burrowing “itch” mite Sarcoptes scabiei , causes significant health problems for children and adults worldwide. Crusted scabies is a particularly severe form of scabies in which mites multiply into the millions, causing extensive skin crusting. The symptoms and signs of scabies suggest host immunity to the scabies mite, but the specific resistant response in humans remains largely uncharacterized. We used 4 scabies mite recombinant proteins with sequence homology to extensively studied house dust mite allergens to investigate a differential immune response between ordinary scabies and the debilitating crusted form of the disease. Subjects with either disease form showed serum IgE against recombinant S. scabiei cysteine and serine proteases and apolipoprotein, whereas naive subjects showed minimal IgE reactivity. Significantly ( P < 0.05) greater serum IgE and IgG4 binding to mite apolipoprotein occurred in subjects with crusted scabies...
Down syndrome (DS) results from trisomy of human chromosome 21 (Hsa21) and is associated with an increased risk of... more
Down syndrome (DS) results from trisomy of human chromosome 21 (Hsa21) and is associated with an increased risk of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD). Here, using the unique transchromosomic Tc1 mouse model of DS we investigate the influence of trisomy of Hsa21 on the protein tau, which is hyperphosphorylated in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. We show that in old, but not young, Tc1 mice increased phosphorylation of tau occurs at a site suggested to be targeted by the Hsa21 encoded kinase, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A). We show that DYRK1A is upregulated in young and old Tc1 mice, but that young trisomic mice may be protected from accumulating aberrantly phosphorylated tau. We observe that the key tau kinase, glycogen synthase kinase3-β (GSK-3β) is aberrantly phosphorylated at an inhibitory site in the aged Tc1 brain which may reduce total glycogen synthase kinase3-β activity. It is possible that a similar mechanism may also occur in people with DS.
Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21... more
Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observations that aneuploidy can cause phenotypes by the mass action of large numbers of genes, with undetectable contributions from individual sequences. The motor abnormalities in DS are relatively understudied-the identity of causative dosage-sensitive genes and the mechanism underpinning the phenotypes are unknown. Using a panel of mouse strains with duplications of regions of mouse chromosomes orthologous to Hsa21 we show that increased dosage of small numbers of genes causes locomotor dysfunction and, moreover, that the Dyrk1a gene is required in three copies to cause the phenotype. Furthermore, we show for the first time a new DS phenotype: loss of motor neurons both in...