Grant Abstract: Nutrition Obesity Research Center (NORC)

Grant Number: 5P30DK056350-17
PI Name: Zeisel
Project Title: Nutrition Obesity Research Center (NORC)

This proposal for supplemental administrative funding to P30 DK56350 (p.i. Zeisel) responds to PA-16-319. The proposal focuses on a dietary supplement (choline) and the mechanisms for its effects on brain development. Though supplementation with choline has important effects on brain development and function, we know very little about the molecular mechanisms underlying the long-term effects of choline supplementation on brain function. Recent work from our laboratory indicates that choline is important for production of a receptor for epidermal growth factor (EGFR), which regulates neural progenitor cell (NPC) maintenance during brain development. Our observations suggest that expression of a specific microRNA (miR-129), which targets Egfr and blocks its protein synthesis, is upregulated in NPCs in response to low choline maternal diet. Disruption of EGFR signaling due to decreased EGFR protein levels in the developing brain results in premature depletion of NPCs and aberrant ratios of different subtypes of cortical neurons – a defect that persists into adulthood. We hypothesize that prenatal choline supplementation modifies expression of a subset of microRNAs (miRs) that are essential for the regulation of NPC proliferative and differentiation capacity. When choline concentrations are low, a subset of miRs become misexpressed in NPCs and disturb neurogenesis, leading to premature depletion of NPCs and defects in the genesis of the cerebral cortex. Conversely, we hypothesize that through regulation of miR expression, supplementation with choline acts to promote proper maintenance of NPCs during development and into adulthood, thus enhancing embryonic and adult neurogenesis and cognitive function. In this study, we will use mouse models to determine 1) which miRs are regulated by choline in cortical NPCs in vivo, and 2) the functional significance of miRs regulated by choline for NPC maintenance and differentiation properties. In Aim 1, we will perform RNA sequencing (RNA Seq) to evaluate changes in the expression of miRs in NPCs isolated from developing brains of embryos from pregnant mice receiving low choline (LC), medium choline (MC) or higher choline (HC) in their drinking water. In Aim 2, we will test the respective functions of candidate miRs, whose expression is regulated by choline availability, in the maintenance and differentiation of NPCs. NPCs will be tested by misexpression in vivo using in utero electroporation technique in mouse embryos Together, these approaches will allow us to identify specific miRs, and their target genes, whose expression in NPCs relies on choline supply, thus filling a gap in our understanding of how this widely available dietary supplement improves brain development and its function throughout life.

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