ANALYSIS OF MID-GESTATION BABOON FRONTAL CORTEX TRANSCRIPTOMES IN FETUSES OF AD LIBITIUM FED (CON) COMPARED TO 70% OF AD LIBITUM FED (NR) MOTHERS

Abstract

Previous work has shown that fetuses of dams fed 70% of the diet consumed by the ad libitum fed controls show an imbalance of apoptotic cell loss in target regions of the frontal cortex for migrating cells compared with controls. In addition, fetuses of nutrient restricted (NR) dams showed a decrease in neurite density and myelination. Taken together these data indicate multiple impairments of cortical development during the first half of gestation. The purpose of this study was to define molecular mechanisms by which NR impacts frontal cortex development in the mid-gestation baboon fetus. Fetal baboon brains were collected at necropsy, the frontal cortex regions dissected and snap frozen from 0.5 gestation (G) CON and NR (n=6 for each group) baboons. Extracted frontal cortex RNA was used to interrogate each transcriptome using human Affymetrix GeneChips. Data were analyzed to identify differential gene expression and differential gene expression in the context of biological pathways. T-tests were used to assess differential gene expression and z-scores (z) to assess differences in biological pathways. Z≥2 was considered significant. Comparison of CON versus NR 0.5G frontal cortex RNA shows 318 significantly differently expressed genes with 157 up- and 161 down-regulated in the NR group. Furthermore, pathway analysis shows significant down-regulation in pathways considered vital to brain development such as: anti-apoptosis (z = 2.41); axonogenesis (z = 3.7); neuron development and differentiation (z = 2.51); extracellular matrix organization and biogenesis (z = 5.07); cell motility (z = 3.85); and regulation of neurogenesis (z = 7.55). Analysis of transcriptome data shows differences between CON and MNR frontal cortex in individual genes and pathways known to be important for developmental processes such as: 1) axonogenesis and neurogenesis, e.g., neuronal cell adhesion molecule (NCAM) and 2) genes known to be important for cell motility, e.g. beta actin and gamma actin. This study is a first step towards understanding the molecular mechanisms that underlie our previously observed alterations in apoptosis, cell proliferation and neurite density that accompany NR. (platform)