Project description:The Dp(10)2Yey mouse carries a ~2.3 Mb intra-chromosomal duplication of mouse chromosome 10 (Mmu10) that makes it an essential model for aspects of Down syndrome (DS, trisomy 21). Specifically, these animals carry extra copies of Mmu10 genes that are homologous to those on human chromosome 21 (Hsa21). Here, we report spatial memory impairment and anxiety-like behaviour in this model alongside altered neural activity in the medial prefrontal cortex (mPFC) and hippocampus (HPC). Specifically, Dp(10)2Yey DS mice showed impaired spatial alternation associated with increased ripple activity in mPFC during the period of memory consolidation, and reduced mobility in a novel environment accompanied by reduced theta-gamma phase-amplitude coupling in HPC. Finally, we found alterations in the number of interneuron subtypes in mPFC and HPC that may contribute to the observed phenotypes and highlight potential approaches to ameliorate the effects of human trisomy 21.
Project description:Down syndrome is characterized by a wide spectrum of clinical signs, which include cognitive and endocrine disorders and haematological abnormalities. Although it is well established that the causative defect of Down syndrome is the trisomy of chromosome 21, the molecular bases of Down syndrome phenotype are still largely unknown. We used the Infinium HumanMethylation450 BeadChip to investigate DNA methylation patterns in whole blood from 29 subjects affected by Down syndrome (DS), using their healthy relatives as controls (mothers and unaffected siblings). This family-based model allowed us to monitor possible confounding effects on DNA methylation patterns deriving from genetic and environmental (lifestyle) factors. The identified epigenetic signature of Down syndrome includes differentially methylated regions that, although enriched on chromosome 21, interest most of the other chromosomes and can be functionally linked to the developmental and haematological defects characteristic of the disease.
Project description:Dysregulation of Sonic hedgehog (SHH) signaling may contribute to multiple Down syndrome-associated phenotypes, including cerebellar hypoplasia, congenital heart defects, craniofacial and skeletal dysmorphologies, and Hirschsprung disease. Granule cell precursors isolated from the developing cerebellum of Ts65Dn mice are less responsive to the mitogenic effects of SHH than euploid cells, and a single postnatal dose of the SHH pathway agonist SAG rescues cerebellar morphology and performance on learning and memory tasks in Ts65Dn mice. SAG treatment also normalizes expression levels of OLIG2 in neural progenitor cells derived from human trisomy 21 iPSCs. However, despite evidence that activating SHH signaling rescues Down syndrome-associated phenotypes, chromosome 21 does not encode any canonical components of the SHH pathway. Here, we screened 163 chromosome 21 cDNAs in a series of SHH-responsive cell lines to identify chromosome 21 genes that modulate SHH signaling and confirmed overexpression of trisomic candidate genes using RNA-seq in Ts65Dn and TcMAC21 cerebellum. Our study indicates that some chromosome 21 genes, including DYRK1A, activate SHH signaling while others, such as HMGN1 and MIS18A, inhibit SHH signaling. Moreover, overexpression of genes involved in chromatin structure and mitosis, but not genes previously implicated in ciliogenesis, regulate the SHH pathway. Our data suggest that cerebellar hypoplasia and other phenotypes related to aberrant SHH signaling arise from the net effect of trisomy for multiple chromosome 21 genes rather than the overexpression of a single trisomic gene. Identifying which chromosome 21 genes modulate SHH signaling may also suggest new therapeutic avenues for ameliorating Down syndrome phenotypes.
Project description:Background: Down syndrome is the most common genetic cause of mental retardation in humans, occurring in ~1 in 800 newborns. It is caused by chromosome 21 trisomy. Disruption of the phenotype is thought to be the result of gene dosage imbalance. The aim of the study was to classify chromosome 21 genes according to their level of expression in Down syndrome. Results: Variations in chromosome 21 gene expression were analyzed in lymphoblastoid cell lines derived from 10 Down syndrome patients and 11 control individuals. Of the 359 genes and predictions displayed on a specifically designed high content chromosome 21 oligoarray, 132 genes were expressed in lymphoblastoid cell lines. By using a powerful statistical analysis, 58 genes were found overexpressed and 42 unchanged in cell lines from Down syndrome patients. Microarray data were validated by quantitative PCR on 10 genes. Conclusions: The 132 chromosome 21 genes expressed by derived lymphoblastoid cell lines were classified into four categories: Class I: 24 genes controlled by the gene dosage effect with an increase in expression in Down syndrome between 1.4 and 1.6; Class II: 14 amplified genes with expression ratio above 1.6; Class III: 32 compensated genes with expression ratio between 0.82 to 1.4 and Class IV: 30 genes with high variability between individuals. Class I and II genes are likely to be involved in the Down syndrome phenotype, in contrast to the compensated Class III genes; Class IV genes could account for the variable phenotypes observed in patients. Keywords: HSA21 gene expression in Down syndrome
Project description:The Ts1Cje mouse model of Down syndrome (DS) has partial triplication of mouse chromosome 16, of which a large portion is homologous to human chromosome 21. We have shown that the number of microglia was decreased in the brain of Ts1Cje fetus, thereby we analyzed the effects of Ts1Cje trisomic region on differentiation of embryonic stem cells (ESCs) with genotype of Ts1Cje mice into primitive macrophages.
Project description:The Ts1Cje mouse model of Down syndrome (DS) has partial triplication of mouse chromosome 16, of which a large portion is homologous to human chromosome 21. We have shown that the number of microglia was decreased in the brain of Ts1Cje fetus, thereby we analyzed the effects of Ts1Cje trisomic region on differentiation of embryonic stem cells (ESCs) with genotype of Ts1Cje mice into primitive macrophage progenitors.
