Abstract
BackgroundEthanol is a potent teratogen. Its adverse neural effects are partly mediated by disrupting fetal neurogenesis. The teratogenic process is poorly understood, and vulnerable neurogenic stages have not been identified. Identifying these is a prerequisite for therapeutic interventions to mitigate effects of teratogen exposures.MethodsWe used flow cytometry and qRT-PCR to screen fetal mouse-derived neurosphere cultures for ethanol-sensitive neural stem cell (NSC) subpopulations, to study NSC renewal and differentiation. The identity of vulnerable NSC populations was validated in vivo, using a maternal ethanol exposure model. Finally, the effect of ethanol exposure on the ability of vulnerable NSC subpopulations to integrate into the fetal neurogenic environment was assessed following ultrasound guided, adoptive transfer.ResultsEthanol decreased NSC mRNAs for c-kit, Musashi-1and GFAP. The CD24+ NSC population, specifically the CD24+CD15+ double-positive subpopulation, was selectively decreased by ethanol. Maternal ethanol exposure also resulted in decreased fetal forebrain CD24 expression. Ethanol pre-exposed CD24+ cells exhibited increased proliferation, and deficits in cell-autonomous and cue-directed neuronal differentiation, and following orthotopic transplantation into naïve fetuses, were unable to integrate into neurogenic niches. CD24depleted cells retained neurosphere regeneration capacity, but following ethanol exposure, generated increased numbers of CD24+ cells relative to controls.ConclusionsNeuronal lineage committed CD24+ cells exhibit specific vulnerability, and ethanol exposure persistently impairs this population’s cell-autonomous differentiation capacity. CD24+ cells may additionally serve as quorum sensors within neurogenic niches; their loss, leading to compensatory NSC activation, perhaps depleting renewal capacity. These data collectively advance a mechanistic hypothesis for teratogenesis leading to microencephaly.
Highlights
Developmental experiences are increasingly recognized to be an important causative factor in adult neuropsychiatric diseases [1]
In both in vitro and in orthotopic adoptive-transfer experiments, we found that ethanol exposure renders the CD24+ subpopulation insensitive to environmental manipulation suggesting that ethanol exposure results in cell-autonomous re-programming of the CD24+ population, and that the underlying mechanisms for programming CD24+ neural stem cell (NSC) perhaps constitute a specific locus for teratogenesis
We screened GD12.5 fetal mouse-derived neurosphere cultures for the expression of mRNA transcripts for transcription factors (Sox9 and Sox3, [46,47]), RNA binding proteins (Musashi-1, [48]) and signaling molecules (c-kit, [49]) that are important for induction of neural identity in stem cells, and the maintenance and renewal of NSCs
Summary
Developmental experiences are increasingly recognized to be an important causative factor in adult neuropsychiatric diseases [1]. Several laboratories have shown that ethanol exposure near the end of the first [9] and second trimester-equivalent period [10,11,12,13,14,15,16] can lead to persistent changes in brain structure These data suggested, but did not show that cells within the fetal neuroepithelium were directly vulnerable to ethanol. We [17,18,19], and others [20,21,22,23] identified fetal neural epithelial cells as a vulnerable target of ethanol, in that ethanol exposure resulted in both immediate and persistent alterations in neuroepithelial renewal and differentiation, importantly, without inducing cell death [17,23,24] This indicates that ethanol does not behave as a toxin in the fetal neuroepithelium, but as a true teratogen. Identifying these is a prerequisite for therapeutic interventions to mitigate effects of teratogen exposures
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