Effects of Dyrk1a and Kcnj6 normalization on the hippocampal transcriptome in the Dp(16)1/Yey mouse model of Down syndrome
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE138468 | GEO | 2020/10/01
REPOSITORIES: GEO
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Project description:Down Syndrome (DS) results from the trisomy of human chromosome 21 (HSA21). It is still the most frequent intellectual disability, affecting 1 newborn per 700 births. Among candidate genes explaining intellectual disabilities seen in DS patients, the dual specificity tyrosine-phosphorylation regulated kinase 1A, DYRK1A, is located in the DS critical region of chromosome 21. DYRK1A has become a major screening target for the development of selective and potent pharmacological inhibitors. We here investigated the effects of a relatively selective DYRK1A inhibitor, Leucettine 41 (hereafter L41) in three different trisomic mouse models with increasing genetic complexity, Tg(Dyrk1a), Ts65Dn and Dp1Yey. Leucettines are derived from the marine sponge alkaloid Leucettamine B.
2018-10-17 | PXD008419 | Pride
Project description:Elevated activity of retrotransposons is increasingly recognized to be implicated in a wide range of neurodegenerative and neurodevelopmental diseases, including Down syndrome (DS), which is the most common chromosomal condition causing intellectual disability globally. Previous research by our group has revealed that treatment with lamivudine, a reverse transcriptase inhibitor, improved neurobehavioral phenotypes and completely rescued hippocampaldependent recognition memory in a DS mouse model, Ts65Dn. We hypothesized that retrotransposition rates would increase in the Ts65Dn mouse model, and lamivudine could block retrotransposons. We analyzed the differentially expressed long interspersed element-1 (LINE-1 or L1) mapping on MMU16 and 17, and showed for the first time that retrotransposition could be associated with Ts65Dn’s pathology, as misregulation of L1 was found in brain tissues associated with trisomy. In the cerebral cortex, 6 out of 26 upregulated L1s in trisomic treated mice were located in the telomeric region of MMU16 near Ttc3, Kcnj6, and Dscam genes. In the hippocampus, one upregulated L1 element in trisomic treated mice was located near the Fgd4 gene on MMU16. Moreover, two downregulated L1s rescued after treatment with lamivudine were located in the intronic region of Nrxn1 (MMU17) and Snhg14 (MMU7), implicated in a variety of neurodegenerative disorders. To gain further insight into the mechanism of this improvement, we here analyzed the gene expression profile in the hippocampus and cerebral cortex of trisomic mice treated and no-treated with lamivudine compared to their wild-type littermates. We found that treatment with lamivudine rescued the expression of 24% of trisomic genes in the cortex (located on mouse chromosome (MMU) 16 and 17) and 15% in the hippocampus (located in the human chromosome 21 orthologous regions), with important DS candidate genes such as App and Ets2, rescued in both regions.
2024-07-11 | GSE252135 | GEO
Project description:Down syndrome is the main genetic cause of intellectual disability and is due to triplication of human chromosome 21 (HSA21). Green tea extracts containing epigallocatechin-3-gallate (green tea) improve cognition both in mouse models and individuals with Down syndrome. We here analyzed the proteome and phosphoproteome alterations in a Down syndrome mouse model, the partial trisomic Ts65Dn mice, and the effect produced by the green tea extract and environmental enrichment (EE). Trisomic hippocampi presented a dysregulated proteome, especially when looking at the phosphorylation level in cognitive-related categories (synaptic proteins, neuronal projection, neuron development, microtubule), and GTPases/kinase activity and chromatin related categories. Green tea, EE, and their phospholipids in the plasma membrane and regulates signal transduction pathways, transcription factors, DNA methylation, mitochondrial function and phosphorylation, and autophagy to exert many of its beneficial biological actions Of interest for DS, it inhibits the activity of the Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase 1A (DYRK1A), a DS candidate gene located in the 21q22.2 human chromosome region4,5. Previous work from our group showed that EGCG partially rescues the effects of overexpression of a DS candidate gene, DYRK1A, on the proteome and phosphoproteome of the hippocampus of TgDyrk1A mice6. However, the extent to which these mechanisms apply to a trisomy scenario is unknown. To get insight in these mechanisms we analyzed changes in protein abundances and phosphorylation in Ts65Dn mice, and their disomic counterparts in baseline conditions and upon three treatments known to improve cognition in Ts65Dn: i) green tea extract containing EGCG, ii) environmental enrichment (EE), and iii) their combination.
2020-10-13 | PXD018515 | Pride
Project description:Congenital heart defects (CHDs) are very frequent in children with Down syndrome (DS), the genetic condition caused by trisomy of chromosome 21 (T21). However, the mechanisms by which T21 causes susceptibility to CHDs are poorly understood. Here, using a combination of human induced pluripotent stem cell (iPSC)-based model and Dp(16)1Yey/+ (Dp16) a mouse model of DS, we identified downregulation of canonical Wnt signaling that is caused by increased dosage of interferon (IFN) receptors encoded on chromosome 21 (HSA21) as a causative factor of CHDs in DS. We differentiated human iPSCs derived from individuals with DS as well as CHDs (DS/CHD iPSCs), and controls (control iPSCs) into cardiac cells. We observed that T21 upregulates IFN signaling, downregulates the canonical WNT pathway, and impairs cardiac differentiation. Furthermore, genetic and pharmacological normalization of IFN pathways restored canonical WNT signaling and rescued defects during cardiac differentiation of DS/CHD iPSCs. Strikingly, treatment with an inhibitor of Janus kinase, which is activated by IFN receptor engagement normalized the canonical Wnt pathway and ameliorated CHDs in Dp16 embryos. Our findings provide new mechanisms underlying CHDs in DS, ultimately aiding the development of novel therapeutic strategies.
2023-06-28 | GSE217557 | GEO
Project description:Analysis of steady-state mRNA levels in adult mouse brain hippocampus at week 17-18 from wild-type C57BL/6J, Dp16, and interferon receptor dosage-normalized Dp16^2xIFNRs mice.
2024-07-18 | GSE272567 | GEO
Project description:The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that DYRK1A binds the SWI/SNF-complex known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1A-dosage imbalance on L1cam. DyrkA dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. We identified a coordinated deregulation of multiple genes that are responsible for the cellular phenotypic traits present in DS such as dendritic growth impairment and microcephaly during prenatal cortex development. Dyrk1a overexpression in primary mouse cortical neurons reduced the neuritic complexity. In the postnatal hippocampus, DYRK1A overexpression suppresses a form of synaptic plasticity that may be sufficient to cause DS cognitive defects. We propose that DYRK1A overexpression-related neuronal gene deregulation generates the brain phenotypic changes that characterize DS, with an accessory role for the gene dosage imbalance of other chromosome 21 genes.
2009-02-23 | GSE14030 | GEO
Project description:The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that DYRK1A binds the SWI/SNF-complex known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1A-dosage imbalance on L1cam. DyrkA dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. We identified a coordinated deregulation of multiple genes that are responsible for the cellular phenotypic traits present in DS such as dendritic growth impairment and microcephaly during prenatal cortex development. Dyrk1a overexpression in primary mouse cortical neurons reduced the neuritic complexity. In the postnatal hippocampus, DYRK1A overexpression suppresses a form of synaptic plasticity that may be sufficient to cause DS cognitive defects. We propose that DYRK1A overexpression-related neuronal gene deregulation generates the brain phenotypic changes that characterize DS, with an accessory role for the gene dosage imbalance of other chromosome 21 genes.
2009-02-23 | GSE14021 | GEO
Project description:The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that DYRK1A binds the SWI/SNF-complex known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1A-dosage imbalance on L1cam. DyrkA dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. We identified a coordinated deregulation of multiple genes that are responsible for the cellular phenotypic traits present in DS such as dendritic growth impairment and microcephaly during prenatal cortex development. Dyrk1a overexpression in primary mouse cortical neurons reduced the neuritic complexity. In the postnatal hippocampus, DYRK1A overexpression suppresses a form of synaptic plasticity that may be sufficient to cause DS cognitive defects. We propose that DYRK1A overexpression-related neuronal gene deregulation generates the brain phenotypic changes that characterize DS, with an accessory role for the gene dosage imbalance of other chromosome 21 genes. Experiment Overall Design: Agilent Whole Mouse Genome oligomicroarrays (GEO accession no. GPL2872, Agilent Technologies, Palo Alto, CA) were used. They contain 60-mer DNA probes synthesized in situ in a 44k format. Of 44,290 spots, 2756 are controls. The remaining 41,534 spots represent 33,661 unique transcripts which correspond to 20,202 unique human genes. Five independent (Dyrk1A overexpression, five individual samples) measurements were carried out for each group of biological conditions using exchanged dye-labeled RNA targets (i.e., Cy3 and Cy5 dye-swapping experiments).
2009-02-27 | E-GEOD-14030 | biostudies-arrayexpress
Project description:Transcription profiling of transgenic down syndrome mouse model to show the role of DYRK1A gene. The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that DYRK1A binds the SWI/SNF-complex known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1Adosage imbalance on L1cam. DyrkA dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. We identified a coordinated deregulation of multiple genes that are responsible for the cellular phenotypic traits present in DS such as dendritic growth impairment and microcephaly during prenatal cortex development. Dyrk1a overexpression in primary mouse cortical neurons reduced the neuritic complexity. In the postnatal hippocampus, DYRK1A overexpression suppresses a form of synaptic plasticity that may be sufficient to cause DS cognitive defects. We propose that DYRK1A overexpression-related neuronal gene deregulation generates the brain phenotypic changes that characterize DS, with an accessory role for the gene dosage imbalance of other chromosome 21 genes.
2009-02-23 | GSE14072 | GEO
Project description:Transcription profiling of transgenic down syndrome mouse model to show the role of DYRK1A gene. The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that DYRK1A binds the SWI/SNF-complex known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1Adosage imbalance on L1cam. DyrkA dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. We identified a coordinated deregulation of multiple genes that are responsible for the cellular phenotypic traits present in DS such as dendritic growth impairment and microcephaly during prenatal cortex development. Dyrk1a overexpression in primary mouse cortical neurons reduced the neuritic complexity. In the postnatal hippocampus, DYRK1A overexpression suppresses a form of synaptic plasticity that may be sufficient to cause DS cognitive defects. We propose that DYRK1A overexpression-related neuronal gene deregulation generates the brain phenotypic changes that characterize DS, with an accessory role for the gene dosage imbalance of other chromosome 21 genes. Transgenic embrionic brain regions versus wild type mice were analysed. The log2 values represent Cy5/Cy3 ratio (transgenic Cy5/wild type Cy3). Each array was scanned under a green laser (543 nm for Cy3 labeling) or a red laser (633 nm for Cy5 labeling) using a ScanArray Lite scanning confocal fuorescent scanner with 10 u resolution (laser power: 85% for Cy5 and 90% for Cy3, gain: 75% for Cy5 and 70% for Cy3). Scanned output files were analyzed using the GenePix Pro 3.0 software. Each spot was defined by automatic positioning of a grid of circles over the image. The average and median pixel intensity ratios calculated from both channels and the local background of each spot were determined. Local background corrected intensity ratios was determined for each spot. The background-corrected expression data were filtered for flagged spots and weak signal. Normalization was performed by the global Lowess method. Studentâs t-test was applied to determine the p value.
2010-05-05 | E-GEOD-14072 | biostudies-arrayexpress