Gene expression profile at single nuclei level of hippocampal neurons from WT and Ts65Dn mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE212351 | GEO | 2022/10/31
REPOSITORIES: GEO
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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:A major challenge in Down syndrome (DS) is to understand how the extra-dose of functional chromosome 21 (HSA21) genetic elements can impact on the tissue-specific transcriptome to contribute to phenotypic alterations. MiRNAs are post-transcriptional modulators with genome-wide regulatory effects. Five microRNAs have been identified in HSA21 that are present in triple copy in DS individuals. Interestingly, in the Ts65Dn mouse model of DS two of these miRNAs, miR-155 and miR-802, are also triplicated resulting in its overexpression. In the current work, we have developed a lentiviral miRNA-sponge genetic strategy for miR-155 and miR-802 (Lv-miR155-802T) to identify novel mRNA targets involved in hippocampal function. Hippocampal injection of the lentiviral sponge in Ts65Dn mice reduced miR-155 and miR-802 overexpression. Noticeable lentiviral sponge rescued the expression of the miRNA predicted targets showing the potential of the strategy to identify miRNA dosage-sensitive genes with potential involvement in DS-hippocampal phenotypes.
2015-05-16 | GSE68074 | GEO
Project description:Background: Despite successful preclinical treatment studies to improve neurocognition in the Ts65Dn mouse model of Down syndrome (DS), translation to humans has failed. This raises questions about the appropriateness of the Ts65Dn mouse as the “gold standard” for DS research. Here we used the novel Ts66Yah mouse that carries both an extra chromosome and the identical segmental Mmu16 trisomy as Ts65Dn without the Mmu17 non-orthologous region. Methods: Forebrains from embryonic day 18.5 Ts66Yah and Ts65Dn mice, along with euploid littermate controls, were used for gene expression and pathway analyses. Behavioral experiments were performed in neonatal and adult mice. Since male Ts66Yah mice are fertile, parent of origin transmission of the extra chromosome was studied. Results: We mapped 45 protein coding genes to the Ts65Dn Mmu17 non-orthologous, among which 71-82 % are expressed during forebrain development. Several of these genes were uniquely overexpressed in Ts65Dn embryonic forebrain; this produced major differences in dysregulated genes and pathways. Despite these genome-wide differences, the primary Mmu16 trisomic effects were highly conserved in both models, resulting in several commonly dysregulated disomic genes and pathways. Delays in motor development, communication and olfactory spatial memory were present in Ts66Yah but more pronounced in Ts65Dn neonates. Adult Ts66Yah mice showed working memory deficits and sex-specific effects in exploratory behavior and spatial hippocampal memory, while long-term memory was preserved. These deficits were milder when compared to Ts65Dn mice. Conclusions: Our findings suggest that triplication of the non-orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may explain why preclinical trials that used this model have unsuccessfully translated to human therapies.
2023-01-16 | GSE222355 | GEO
Project description:To understand the molecular basis of Down syndrome pathogenesis, we performed a transcriptome analysis of nine different tissues in Ts65Dn, an established mouse model of human trisomy 21. Ts65Dn mice have segmental trisomy of mouse chromosome 16 with ca. 128 genes at dosage imbalance (Reeves et al. 1995). The Ts65Dn mouse is widely used as a model for studies of DS because it is at dosage imbalance for the orthologs of about half the 284 Chr21 genes. Ts65Dn mice have several features that directly parallel developmental anomalies of DS. We compare here the expression of 136 mouse orthologs of Chr21 genes, 77 of which are triplicated in Ts65Dn, in trisomic and euploid mice. <br> <br> We designed a mouse cDNA expression array interrogating 136 mmu21 genes. RNA pools from four adult male Ts65Dn mice and four male euploid littermates were prepared from cortex and dissected from three to four month-old mice. Directly labeled first strand cDNA probes from nine different tissues were hybridized to the arrays in replicated hybridizations. A total of 446 genes that are not triplicated in Ts65Dn mice served as controls. These included 62 mmu21 genes from MMU10, MMU17, and non-triplicated portions of MMU16, plus 384 randomly distributed mouse cDNAs from the Unigene collection.
2004-04-23 | E-MEXP-102 | biostudies-arrayexpress
Project description:Down syndrome (DS), a genetic condition leading to intellectual disability, is characterized by triplication of human chromosome 21. Neuropathological hallmarks of DS include abnormal central nervous system development that manifests during gestation and extends throughout life. As a result, newborns and adults with DS exhibit cognitive and motor deficits and fail to meet typical developmental and lack independent life skills. A critical outstanding question is how DS-specific prenatal and postnatal phenotypes are recapitulated in different mouse models. To begin answering this question, we developed a life span approach to directly compare differences in embryonic brain development, cellularity, gene expression, neonatal and adult behavior behavior in three cytogenetically distinct mouse models of DS—Ts1Cje, Ts65Dn and Dp16/1Yey (Dp16). In the last two decades multiple therapeutic trials have been attempted to improve cognition in humans with DS but the results of these interventions lacked efficacy despide their succes in the Ts65Dn mouse model of DS. To better understand how phenotypic changes in humans in DS are recapitulated in different mouse models, we copared embryonic brain development and gene expression, perinatal behavior and brain excitatoty/inhibitory cell distribution, and adult behavior and gene expression in the Dp16, Ts65Dn and Ts1Cje mouse models of DS. The objectives of this study were to determine the best model(s) for prenatal and postnatal therapeutic trials and to identify treatment endpoints that can be used to evaluate the fficacy of these therapies prior to human clinical trials. Our data showed that, at embryonic day 15.5, Ts65Dn mice are the most profoundly and consistently affected with respect to somatic growth, brain morphogenesis, and neurogenesis compared to Ts1Cje and Dp16 embryos. However, gene expression results show that both Ts65Dn and Ts1Cje embryonic forebrains have a relatively high number of differentially expressed genes compared to Dp16, with little overlap in gene identities and genomic distribution observed among these models. Additionally, postnatal histological analyses show varying degrees of cell population and brain histogenesis abnormalities among the three strains. Behavioral testing also highlights differences among the models in their ability to meet various developmental milestones. At adulthood, Ts65Dn and Ts1Cje showed hyperactive behavior in the open field test but not Dp16 mice. In the fear conditioning test, all three strains showed lower freezing versus eupploid mice; Dp16 were the most severely affected. In the Morris water maze, Ts65Dn showed significant delays in the hidden platform, probe and reversal trials. Dp16 mice showed milder deficits in the hidden platform trial but severe deficits in reversal. Ts1Cje mice had no spatial memory deficits. In the rotarod test, Dp16 performed poorly in fixed and accelerating speed trials, while Ts1Cje was only abnormal at high speeds. Ts65Dn rotarod performance was unaffected. Compared to euploid, Ts65Dn had a higher number of differentially expressed (DEX) genes in cortex and cerebellum, while Ts1Cje had more DEX genes in hippocampus and cerebellum. Dp16 had the lowest number of DEX genes in all regions analyzed. Pathway analyses highlighted commonly dysregulated pathways, including G-protein signaling, oxidative stress, interferon signaling, glycosylation and disulfide bonds.
2017-05-23 | GSE99135 | GEO
Project description:A major challenge in Down syndrome (DS) is to understand how the extra-dose of functional chromosome 21 (HSA21) genetic elements can impact on the tissue-specific transcriptome to contribute to phenotypic alterations. MiRNAs are post-transcriptional modulators with genome-wide regulatory effects. Five microRNAs have been identified in HSA21 that are present in triple copy in DS individuals. Interestingly, in the Ts65Dn mouse model of DS two of these miRNAs, miR-155 and miR-802, are also triplicated resulting in its overexpression. In the current work, we have developed a lentiviral miRNA-sponge genetic strategy for miR-155 and miR-802 (Lv-miR155-802T) to identify novel mRNA targets involved in hippocampal function. Hippocampal injection of the lentiviral sponge in Ts65Dn mice reduced miR-155 and miR-802 overexpression. Noticeable lentiviral sponge rescued the expression of the miRNA predicted targets showing the potential of the strategy to identify miRNA dosage-sensitive genes with potential involvement in DS-hippocampal phenotypes. Euploid and trisomic adult mice were bilaterally injected at the level of the ventral hippocampus at selected coordinates (AP=-3.3mm, L=+/- 3mm, DV=-3.3mm and -2.3mm relative to bregma). Up to 108 transducing units (3µl of viral suspensions of Lv-Contol or Lv-miR155-802T) were injected into each hemisphere at a rate of 0.2 µl/min, under the precise control of an infusion pump (Ultramicropump, World Precision Instruments). Mice were euthanized for hippocampus collection at day 23 after administration. Transcriptome of hippocampus of euploid and trisomic mice treated with Lv-Control or Lv-miR155-802T was analysed using an Agilent SurePrint G3 Mouse gene expression 8x60K Microarray (ID 028005). A total RNA 100 ng, obtained using miRNeasy Mini Ki (QIAGEN), were labeled using LowInputQuick Amp Labeling kit (Agilent 5190-2305) following manufacturer instructions. Briefly, mRNA was reverse transcribed in the presence of T7-oligo-dT primer to produce cDNA. cDNA was then in vitro transcribed with T7 RNA polymerase in the presence of Cy3-CTP to produce labeled cRNA. The labeled cRNA was hybridized to the Agilent SurePrint G3 Mouse gene expression 8x60K Microarray (ID 028005) according to the manufacturer's protocol. The arrays were washed, and scanned on an Agilent G2565CA microarray scanner at 100% PMT and 3µm resolution. Intensity data was extracted using the Feature Extraction software (Agilent). Replicates from each genotypes and treatment group were distributed as follows: EU+Lv-Contol n=4, EU+Lv-miR155-802T n=4, TS+Lv-Contol n=5, TS+Lv-miR155-802T n=3.
2015-05-16 | E-GEOD-68074 | biostudies-arrayexpress
Project description:Persons with Down syndrome (DS) exhibit low muscle strength that significantly impairs their physical functioning. The Ts65Dn mouse model of DS also exhibits muscle weakness in vivo and may serve as a useful model to examine potential factors responsible for DS-associated muscle dysfunction. Therefore, the purpose of this experiment was to directly assess skeletal muscle function in the Ts65Dn mouse and to reveal potential mechanisms of DS-associated muscle weakness. Soleus muscles were harvested from anesthetized male Ts65Dn and wild-type (WT) colony controls. In vitro muscle contractile experiments revealed normal force generation of unfatigued Ts65Dn soleus, but a 12% reduction in force was observed in Ts65Dn muscle during recovery following fatiguing contractions compared to WT muscle (p<0.05). Oxidative stress may contribute to DS-related pathologies, including muscle weakness, which may be the result of overexpression of chromosome 21 genes (e.g., copper-zinc superoxide dismutase (SOD1)). SOD1 expression was 25% higher (p<0.05) in Ts65Dn soleus compared to WT muscle but levels of other antioxidant proteins were unchanged. Lipid peroxidation (4-hydroxynoneal) was unaltered in Ts65Dn muscle although protein carbonyls were 20% greater compared to muscle of WT animals (p<0.05). Cytochrome c oxidase expression was reduced 22% in Ts65Dn muscle, suggesting a limitation in mitochondrial function may contribute to post-fatigue muscle weakness. Microarray analysis of Ts65Dn soleus revealed alteration of numerous cellular pathways including: proteolysis, glucose and fat metabolism, neuromuscular transmission, and ATP biosynthesis. In summary, the Ts65Dn mouse displays evidence of muscle dysfunction, and the potential role of mitochondria and oxidative stress warrants further investigation. We used microarrays to gain insight into potential mechanisms of DS-associated skeletal muscle weakness. Soleus muscles were obtained from four male Ts65Dn (DS) mice and four male colony control mice. Animals were apparently healthy and approximately five months old. The muscles were harvested in the basal state under anesthesia induced by sodium pentobarbital at approximately the same time of the day.
2013-01-06 | E-GEOD-39159 | biostudies-arrayexpress
Project description:This project aims to identify transcriptomic changes in the Down Syndrome mouse model (Ts65Dn) in two brain regions, hippocampus and preoptic area. Also, we aim to identify possible transcriptomics rescue effect in Ts55Dn with viral-mediated overexpression of miR200. In total, we have 3 groups of hippocampal and 3 groups of preotic area tissue (WT control virus, 65Dn control virus and 65Dn miR200 - N=4 per group).
2023-05-23 | GSE199974 | GEO
Project description:Persons with Down syndrome (DS) exhibit low muscle strength that significantly impairs their physical functioning. The Ts65Dn mouse model of DS also exhibits muscle weakness in vivo and may serve as a useful model to examine potential factors responsible for DS-associated muscle dysfunction. Therefore, the purpose of this experiment was to directly assess skeletal muscle function in the Ts65Dn mouse and to reveal potential mechanisms of DS-associated muscle weakness. Soleus muscles were harvested from anesthetized male Ts65Dn and wild-type (WT) colony controls. In vitro muscle contractile experiments revealed normal force generation of unfatigued Ts65Dn soleus, but a 12% reduction in force was observed in Ts65Dn muscle during recovery following fatiguing contractions compared to WT muscle (p<0.05). Oxidative stress may contribute to DS-related pathologies, including muscle weakness, which may be the result of overexpression of chromosome 21 genes (e.g., copper-zinc superoxide dismutase (SOD1)). SOD1 expression was 25% higher (p<0.05) in Ts65Dn soleus compared to WT muscle but levels of other antioxidant proteins were unchanged. Lipid peroxidation (4-hydroxynoneal) was unaltered in Ts65Dn muscle although protein carbonyls were 20% greater compared to muscle of WT animals (p<0.05). Cytochrome c oxidase expression was reduced 22% in Ts65Dn muscle, suggesting a limitation in mitochondrial function may contribute to post-fatigue muscle weakness. Microarray analysis of Ts65Dn soleus revealed alteration of numerous cellular pathways including: proteolysis, glucose and fat metabolism, neuromuscular transmission, and ATP biosynthesis. In summary, the Ts65Dn mouse displays evidence of muscle dysfunction, and the potential role of mitochondria and oxidative stress warrants further investigation.
2013-01-06 | GSE39159 | GEO
Project description:With an astounding incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in Down syndrome neurons and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.
2022-09-21 | GSE210117 | GEO