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 post-natal neurocognition.

An Integrated Human/Murine Transcriptome and Pathway Approach To Identify Prenatal Treatments For Down Syndrome

“…Only 33 Mmu 16 genes in Ts1Cje (out of 77 trisomic genes), 46 genes in Ts65Dn (out of 128 trisomic genes) and 19 in Dp16 (out of 145 trisomic genes) were differentially-regulated1222. Our studies have been corroborated by other groups that reported up-regulation of only a subset of Mmu 16 triplicated genes in the developing Ts1Cje cerebellum and tissues from Ts65Dn, including brain and heart2324252627.…”

Perinatal Natural History of the Ts1Cje Mouse Model of Down Syndrome: Growth Restriction, Early Mortality, Heart Defects, and Delayed Development

“…For each reaction, Fez -F/ Fez -R primers were used as endogenous controls. PCR conditions and amplification were as previously described [15]. Primer information and amplicon sizes are shown in the S1 Supplementary Methods.…”

“…The Ts1Cje mouse model contains a reciprocal translocation with a smaller trisomic region (77 genes) than Ts65Dn and a monosomy of the distal part of chromosome 12 (7 genes), but it has some comparable, although milder, behavioral and cognitive deficits [7, 8, 13–15]. In contrast to Ts65Dn, Ts1Cje males are fertile [7].…”

“…We have previously published data on the embryonic brain transcriptome and neonatal behavioral abnormalities in Ts1Cje mice [15]. In the course of performing the prior experiments we noted neonatal deaths and wondered whether these were associated with the Ts1Cje genotype?…”

8: Males are from Mars, females are from Venus: sex-specific fetal brain gene expression signatures in a mouse model of maternal diet-induced obesity

“…A recent study of fetal brain gene expression in a mouse model of Down syndrome found similarly modest fold changes, and an abnormal neurobehavioral phenotype in pups. 37 …”