Abstract
ABSTRACTEthanol exposure during pregnancy is an established cause of birth defects, including neurodevelopmental defects. Most adult neurons are produced during the second trimester-equivalent period. The fetal neural stem cells (NSCs) that generate these neurons are an important but poorly understood target for teratogenesis. A cohort of miRNAs, including miR-153, may serve as mediators of teratogenesis. We previously showed that ethanol decreased, while nicotine increased miR-153 expression in NSCs. To understand the role of miR-153 in the etiology of teratology, we first screened fetal cortical NSCs cultured ex vivo, by microarray and quantitative RT-PCR analyses, to identify cell-signaling mRNAs and gene networks as important miR-153 targets. Moreover, miR-153 over-expression prevented neuronal differentiation without altering neuroepithelial cell survival or proliferation. Analysis of 3′UTRs and in utero over-expression of pre-miR-153 in fetal mouse brain identified Nfia (nuclear factor-1A) and its paralog, Nfib, as direct targets of miR-153. In utero ethanol exposure resulted in a predicted expansion of Nfia and Nfib expression in the fetal telencephalon. In turn, miR-153 over-expression prevented, and partly reversed, the effects of ethanol exposure on miR-153 target transcripts. Varenicline, a partial nicotinic acetylcholine receptor agonist that, like nicotine, induces miR-153 expression, also prevented and reversed the effects of ethanol exposure. These data collectively provide evidence for a role for miR-153 in preventing premature NSC differentiation. Moreover, they provide the first evidence in a preclinical model that direct or pharmacological manipulation of miRNAs have the potential to prevent or even reverse effects of a teratogen like ethanol on fetal development.
Highlights
Transfection with the miR-153 expression construct resulted in significant over-expression of miR-153, within the range of miRNA expression observed in Neural stem cells (NSCs)
HDAC8 lacks a predicted miR-153 target site within its 39UTR, but we examined its expression following miR-153 over-expression because it is the earliest type-1 HDAC to be expressed during neurogenesis in the fetal murine telencephalon (Murko et al, 2010) and is implicated in the etiology of the Wilson–Turner X-linked (Harakalova et al, 2012) and Cornelia de Lange (Deardorff et al, 2012) syndromes, both of which are characterized by cognitive impairment
Ethanol disrupts the expression pattern of Nfia and Nfib in mouse fetal brains We previously showed that ethanol exposure resulted in decreased miR-153 expression in NSCs (Balaraman et al, 2012; Sathyan et al, 2007)
Summary
Maternal ethanol exposure during this neurogenic period has been shown to result in fetal brain growth deficits (Kotkoskie and Norton, 1989; Miller and Nowakowski, 1991; Sudheendran et al, 2013). These deficits were not due to NSC death, but rather due to NSC depletion by loss of renewal and premature maturation (Prock and Miranda, 2007; Santillano et al, 2005; Tingling et al, 2013)
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