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Analysis of the Fetal and Neonatal Transcriptomic and Neurocognitive Phenotype in the Ts1Cje Mouse Model of Down syndrome

ABSTRACT: 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.

ORGANISM(S): Mus musculus  

SUBMITTER: Heather C Wick   Donna K Slonim  Faycal Guedj  Lea C Graham  Millie A Ferres  Klaus A Miczek  Diana W Bianchi  Jeroen L Pennings 

PROVIDER: E-GEOD-62538 | ArrayExpress | 2014-11-15



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