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miR-153 and miR-335, Ethanol Sensitive MicroRNAs, Control NSC/NPC Maturation during Fetal Brain Development

Tsai, PC;

Maternal alcohol consumption during pregnancy, especially during the first and second trimester, can cause the wide range of severe birth defects classified as fetal alcohol spectrum disorder (FASD). FASD is a wide spectrum disease characterized by delayed fetal growth, facial abnormalities, and cognitive and behavioral deficits of the central nervous system. The cost of FASD to the U.S. healthcare system is estimated at more than $6 billion annually, suggesting the problem of maternal consumption is increasing through years. Previous research by Sathyan and his colleague has shown that only few miRNAs, miR-9, miR-21, miR-153, and miR-335, were able to mediate ethanol’s teratogenic effects through regulation neural stem/progenitor cell (NSC/NPC). However, the mechanisms whereby miRNAs mediate fetal neural stem cell (NSC) vulnerability and contribute to ethanol’s teratology are complex and still unclear. Therefore, the goal of my dissertation is to discover novel pathways of two miRNAs, miR-153 and miR-335, as key modulators of ethanol. Data from the miR-153 study identified NFIA (nuclear factor-1A) and its paralog, NFIB, as direct targets of miR-153 ex vivo as well as in vivo, and miR-153 overexpression prevented neuronal differentiation. MiR-153 functional analysis in neurospheres suggested that overexpression of this microRNA prevented, and partly reversed ethanol’s teratogenic effects on miR-153 target transcripts. This antagonistic effect was also found in the pharmacology studies using varenicline, a FDA-approved drug as a partial nicotinic acetylcholine receptor agonist, which increased miR-153 expression. These data collectively suggested a role for miR-153 in preventing NSCs/NPCs differentiation, and showed that direct or pharmacological manipulation of miRNAs in an ex vivo model have the potential capability to prevent or even reverse ethanol’s effects on fetal brain development. Data from miR-335 research presented show that miR-335 regulates NSCs/NPCs markers DCX, NeuroD1, and c-Kit, and that miR-335 dysregulation results in neuronal premature-maturation via increasing asymmetric cell divisions, driving neuronal early differentiation through inducing stem cell genes DCX and NeuroD1 in the ventricular zone (VZ) of the developing cortex. In sum, my data conclude that miR-335 and miR-153 act as molecular brakes to prevent NSCs/NPCs early maturation by regulating cell differentiation genes during the second trimester, and ethanol leads to organizational defects in the developing cerebral cortex through driving premature-maturation. In addition, preliminary data from miRNA functional studies indicate that misregulation of miRNA-regulated genes by ethanol exposure can be prevented or reversed in the presence of microRNAs or specific pharmaceuticals. This evidence explores the application of candidate miRNAs, as well as other medical drugs, as potential therapeutics to overcome ethanol’s teratology.