title: The fetal brain transcriptome and neonatal behavioral phenotype in the Ts1Cje mouse model of Down syndrome.
abstract: Human fetuses with Down syndrome demonstrate abnormal brain growth and reduced neurogenesis. Despite the prenatal onset of the phenotype, most therapeutic trials have been conducted in adults. Here, we present evidence for fetal brain molecular and neonatal behavioral alterations in the Ts1Cje mouse model of Down syndrome. Embryonic day 15.5 brain hemisphere RNA from Ts1Cje embryos (n = 5) and wild type littermates (n = 5) was processed and hybridized to mouse gene 1.0 ST arrays. Bioinformatic analyses were implemented to identify differential gene and pathway regulation during Ts1Cje fetal brain development. In separate experiments, the Fox scale, ultrasonic vocalization and homing tests were used to investigate behavioral deficits in Ts1Cje pups (n = 29) versus WT littermates (n = 64) at postnatal days 3-21. Ts1Cje fetal brains displayed more differentially regulated genes (n = 71) than adult (n = 31) when compared to their age-matched euploid brains. Ts1Cje embryonic brains showed up-regulation of cell cycle markers and down-regulation of the solute-carrier amino acid transporters. Several cellular processes were dysregulated at both stages, including apoptosis, inflammation, Jak/Stat signaling, G-protein signaling, and oxidoreductase activity. In addition, early behavioral deficits in surface righting, cliff aversion, negative geotaxis, forelimb grasp, ultrasonic vocalization, and the homing tests were observed. The Ts1Cje mouse model exhibits abnormal gene expression during fetal brain development, and significant neonatal behavioral deficits in the pre-weaning period. In combination with 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.
authors.affiliation: Mother Infant Research Institute, Tufts Medical Center and the Floating Hospital for Children, Boston, Massachusetts.
authors.forename: Faycal
authors.initials: F
authors.lastname: Guedj
authors.affiliation: Center for Health Protection (GZB), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors.forename: Jeroen L A
authors.initials: JL
authors.lastname: Pennings
authors.affiliation: Mother Infant Research Institute, Tufts Medical Center and the Floating Hospital for Children, Boston, Massachusetts.
authors.forename: Millie A
authors.initials: MA
authors.lastname: Ferres
authors.affiliation: Mother Infant Research Institute, Tufts Medical Center and the Floating Hospital for Children, Boston, Massachusetts.
authors.forename: Leah C
authors.initials: LC
authors.lastname: Graham
authors.affiliation: Department of Computer Science, Tufts University, Medford, Massachusetts.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Wick
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts.
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Miczek
authors.affiliation: Department of Computer Science, Tufts University, Medford, Massachusetts.
authors.forename: Donna K
authors.initials: DK
authors.lastname: Slonim
authors.affiliation: Mother Infant Research Institute, Tufts Medical Center and the Floating Hospital for Children, Boston, Massachusetts.
authors.forename: Diana W
authors.initials: DW
authors.lastname: Bianchi
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005333:Fetus / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000235:genetics; D010641:Phenotype; D011247:Pregnancy; D059467:Transcriptome / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
keywords: Down syndrome; embryonic brain; gene expression; genotype/phenotype correlation; neonatal behavior; systems biology