Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that are involved in various biological processes, including apoptosis, by regulating gene expression. This study was designed to test the hypothesis that ethanol-induced downregulation of miR-135a contributes to ethanol-induced apoptosis in neural crest cells (NCCs) by upregulating Siah1 and activating the p38 mitogen-activated protein kinase (MAPK)/p53 pathway. We found that treatment with ethanol resulted in a significant decrease in miR-135a expression in both NCCs and zebrafish embryos. Ethanol-induced downregulation of miR-135a resulted in the upregulation of Siah1 and the activation of the p38 MAPK/p53 pathway and increased apoptosis in NCCs and zebrafish embryos. Ethanol exposure also resulted in growth retardation and developmental defects that are characteristic of fetal alcohol spectrum disorders (FASD) in zebrafish. Overexpression of miRNA-135a significantly reduced ethanol-induced upregulation of Siah1 and the activation of the p38 MAPK/p53 pathway and decreased ethanol-induced apoptosis in NCCs and zebrafish embryos. In addition, ethanol-induced growth retardation and craniofacial defects in zebrafish larvae were dramatically diminished by the microinjection of miRNA-135a mimics. These results demonstrated that ethanol-induced downregulation of miR-135a contributes to ethanol-induced apoptosis in NCCs by upregulating Siah1 and activating the p38 MAPK/p53 pathway and that the overexpression of miRNA-135a can protect against ethanol-induced apoptosis in NCCs and craniofacial defects in a zebrafish model of FASD.
Highlights
Fetal alcohol spectrum disorder (FASD) is an umbrella term used to describe the range of disorders that occur in an individual whose mother drinks alcohol during pregnancy
Multiple signaling pathways have been reported to be involved in ethanol-induced apoptosis, including B-cell lymphoma 2 (Bcl-2) (Hong et al, 2002), p53 (Jana et al, 2010), nuclear factor-like 2 (Nrf2) (Chen et al, 2013a), p38 mitogen-activated protein kinase (MAPK), and seven in absentia homolog 1 (Siah1) (Yuan et al, 2017)
Our previous study has demonstrated that ethanol treatment can significantly increase the expression and nuclear translocation of Siah1 in neural crest cells (NCCs) and that Siah1 signaling plays a critical role in ethanol-induced apoptosis in NCCs (Sun et al, 2014)
Summary
Fetal alcohol spectrum disorder (FASD) is an umbrella term used to describe the range of disorders that occur in an individual whose mother drinks alcohol during pregnancy. Multiple signaling pathways have been reported to be involved in ethanol-induced apoptosis, including B-cell lymphoma 2 (Bcl-2) (Hong et al, 2002), p53 (Jana et al, 2010), nuclear factor (erythroid-derived 2)-like 2 (Nrf2) (Chen et al, 2013a), p38 mitogen-activated protein kinase (MAPK), and seven in absentia homolog 1 (Siah1) (Yuan et al, 2017). Our previous study has demonstrated that ethanol treatment can significantly increase the expression and nuclear translocation of Siah in NCCs and that Siah signaling plays a critical role in ethanol-induced apoptosis in NCCs (Sun et al, 2014). We have shown that ethanol-induced upregulation of Siah can induce apoptosis in NCCs through p38 MAPK-mediated activation of the p53 signaling pathway (Yuan et al, 2017). The mechanisms by which ethanol upregulates Siah in NCCs are not clear
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