PRENATAL ALCOHOL EXPOSURE AND THE DEVELOPING BRAIN LONG NON-CODING RNA MECHANISMS & TRANSCRIPTOMIC CHANGES

Abstract

Fetal alcohol exposure is the leading non-genetic cause of neurodevelopmental disabilities. In the introduction, I first survey common genetic, epigenetic and environmental causes of neurodevelopmental disorders, and specifically, fetal alcohol syndrome. Next, I review the literature long non-coding RNA classes with a focus on pseudogenes. Finally, I survey single-cell RNA sequencing methods as a means to understand the effects of teratogens like alcohol on the developing brain. In the first studies of my dissertation, I utilize a neural stem cell culture model to study the effects of alcohol (ethanol) exposure on a novel pseudogene family member of the pluripotency factor Oct4/Pou5f1. This pseudogene locus, mOct4pg9, is transcribed into a long non-coding RNA. Alcohol exposure resulted in its upregulation in neural progenitor cells and I show that its upregulation mediates alcohol’s pro-maturation effects on neural progenitor cells. In the second part, I utilize a mouse model of single binge dose prenatal alcohol exposure and study cell-type specific effects of alcohol exposure on fetal cortex development. In this section, I identify fetal sex-specific cell-type specific prenatal alcohol effects in the fetal developing cortex, including effects mediated by the loss of a long non-coding RNA, Xist, resulting in loss of X-chromosome inactivation.