Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression data from postnatal mouse brain regions of Ts1Cje and disomic C57BL/6 mice.

ABSTRACT: The Ts1Cje mouse model of Down syndrome (DS) has partial triplication of mouse chromosome 16 (MMU16), which is partially homologous to human chromosome 21. The mouse model develops various neuropathological features identified in DS individuals. We analysed the effect of partial triplication of the MMU16 segment on global gene expression in the cerebral cortex, cerebellum and hippocampus of Ts1Cje mice at 4 time-points; postnatal day (P)1, P15, P30 and P84. RNA was extracted from thre brain regions (Cerebral cortex, hippocampus and cerebellum) for hybridization to arrays from 3 pairs of Ts1Cje and disomic C57BL/6 littermate control for each timepoints at postnatal (P) day 1, P15, P30 and P84.

ORGANISM(S): Mus musculus

SUBMITTER: King Hwa Ling

PROVIDER: E-GEOD-49050 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Functional transcriptome analysis of the postnatal brain of the Ts1Cje mouse model for Down syndrome reveals global disruption of interferon-related molecular networks.

Ling King-Hwa KH Hewitt Chelsee A CA Tan Kai-Leng KL Cheah Pike-See PS Vidyadaran Sharmili S Lai Mei-I MI Lee Han-Chung HC Simpson Ken K Hyde Lavinia L Pritchard Melanie A MA Smyth Gordon K GK Thomas Tim T Scott Hamish S HS

BMC genomics 20140722

<h4>Background</h4>The Ts1Cje mouse model of Down syndrome (DS) has partial triplication of mouse chromosome 16 (MMU16), which is partially homologous to human chromosome 21. These mice develop various neuropathological features identified in DS individuals. We analysed the effect of partial triplication of the MMU16 segment on global gene expression in the cerebral cortex, cerebellum and hippocampus of Ts1Cje mice at 4 time-points: postnatal day (P)1, P15, P30 and P84.<h4>Results</h4>Gene expre ...[more]

PMID: 25052193

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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.

Project description:Down syndrome is characterized by a complex phenotype that includes developmental disabilities and congenital anomalies emerging during fetal life. The molecular origin of these abnormalities is poorly understood. Despite the evidence of prenatal onset of the phenotype, most therapeutic trials have been conducted in affected adults. This study presents evidence for fetal brain molecular and neonatal behavioral abnormalities in the Ts1Cje mouse model of Down syndrome. Gene expression changes were more pronounced in the Ts1Cje fetal brains than adult cerebral cortex and hippocampus. Functional pathway analyses showed that Ts1Cje embryonic brains display significant up-regulation of cell cycle and down-regulation of Solute-carrier amino acid transport pathways. Several cellular processes, including apoptosis, inflammation, Jak/Stat signaling, G-protein signaling and oxidoreductase activity were consistently dysregulated at both stages. Fetal brain gene expression changes were associated with early behavioral deficits in surface righting, cliff aversion, negative geotaxis, forelimb grasp, ultrasonic vocalization and homing tests. In combination with the human studies, this suggests that the Down syndrome phenotype manifests prenatally and provides a rationale for prenatal therapy to improve perinatal brain development and postnatal neurocognition. In the present study, we demonstrated that significant gene expression abnormalities were already present in the embryonic day 15 forebrain of the Ts1Cje mouse model of DS. The abnormal Ts1Cje embryonic molecular signature was associated with early postnatal developmental milestones and behavioral changes. These data provide a comprehensive picture of the genotype-phenotype relationship the Ts1Cje model of Down syndrome. We analyzed the forebrain whole transcriptome from embryonic day 15.5 (E15.5) Ts1Cje (n=5) and wild-type (n=5) using Affymetrix mouse gene 1.0 ST array. Data were normalized and analyzed to identify and accurately map genes that are significantly differentially expressed. Functional analyses were performed using GSEA and DAVID and DFLAT to better characterize cellular processes and pathways that are consistently affected in both brain regions. In separate experiments, the Fox scale, ultrasonic vocalization and homing tests were used to investigate postnatal behavioral deficits in Ts1Cje pups (n=29) versus WT littermates (n=64) at days 3 to 21.

Dataset Information

Expression data from postnatal mouse brain regions of Ts1Cje and disomic C57BL/6 mice.

Publications

Functional transcriptome analysis of the postnatal brain of the Ts1Cje mouse model for Down syndrome reveals global disruption of interferon-related molecular networks.

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