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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Competing interactions between micro-RNAs determine neural progenitor survival and proliferation after ethanol exposure: evidence from an ex vivo model of the fetal cerebral cortical neuroepithelium.
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Competing interactions between micro-RNAs determine neural progenitor survival and proliferation after ethanol exposure: evidence from an ex vivo model of the fetal cerebral cortical neuroepithelium.

机译：micro-RNA之间的竞争性相互作用决定了乙醇暴露后神经祖细胞的存活和增殖：来自胎儿大脑皮质神经上皮的离体模型的证据。

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摘要

The fetal brain is sensitive to a variety of teratogens, including ethanol. We showed previously that ethanol induced mitosis and stem cell maturation, but not death, in fetal cerebral cortex-derived progenitors. We tested the hypothesis that micro-RNAs (miRNAs) could mediate the teratogenic effects of ethanol in a fetal mouse cerebral cortex-derived neurosphere culture model. Ethanol, at a level attained by alcoholics, significantly suppressed the expression of four miRNAs, miR-21, -335, -9, and -153, whereas a lower ethanol concentration, attainable during social drinking, induced miR-335 expression. A GABA(A) receptor-dependent mechanism mediated miR-21, but not miR-335 suppression, suggesting that divergent mechanisms regulate ethanol-sensitive miRNAs. Antisense-mediated suppression of miR-21 expression resulted in apoptosis, suggesting that miR-21 is an antiapoptotic factor. miR-335 knockdown promoted cell proliferation and prevented death induced by concurrently suppressing miR-21, indicating that miR-335 is a proapoptotic, antimitogenic factor whose actions are antagonistic to miR-21. Computational analyses identified two genes, Jagged-1, a Notch-receptor ligand, and embryonic-lethal abnormal vision, Drosophila-like 2 (ELAVL2), a brain-specific regulator of RNA stability, as presumptive targets of three of four ethanol-sensitive micro-RNAs. Combined knockdown of miR-335, -21, and -153 significantly increased Jagged-1 mRNA. Furthermore, ethanol induced both Jagged-1 and ELAVL2 mRNA. The collective suppression of micro-RNAs is consistent with ethanol induction of cell cycle and neuroepithelial maturation in the absence of apoptosis. These data identify a role for micro-RNAs as epigenetic intermediaries, which permit teratogens to shape complex, divergent developmental processes, and additionally demonstrate that coordinately regulated miRNAs exhibit both functional synergy and antagonism toward each other.
机译：胎儿大脑对多种致畸剂敏感，包括乙醇。我们之前表明，乙醇诱导胎儿大脑皮层衍生祖细胞的有丝分裂和干细胞成熟，但不诱导死亡。我们测试了 micro-RNA （miRNA） 可以介导胎儿小鼠大脑皮层衍生的神经球培养模型中乙醇致畸作用的假设。酗酒者达到的乙醇水平显着抑制了四种 miRNA 的表达，即 miR-21、-335、-9 和 -153，而在社交饮酒期间可达到的较低乙醇浓度诱导 miR-335 表达。GABA（A） 受体依赖性机制介导了 miR-21，但不介导 miR-335 抑制，这表明不同的机制调节乙醇敏感的 miRNA。反义介导的 miR-21 表达抑制导致细胞凋亡，表明 miR-21 是一种抗凋亡因子。敲低 miR-335 促进细胞增殖并防止同时抑制 miR-21 诱导的死亡，表明 miR-335 是一种促凋亡、抗有丝分裂因子，其作用与 miR-21 拮抗。计算分析确定了两个基因，Jagged-1，一种Notch受体配体，以及胚胎致死性异常视力，果蝇样2（ELAVL2），一种RNA稳定性的大脑特异性调节因子，作为四种乙醇敏感micro-RNA中的三种的推定靶标。miR-335、-21 和 -153 的联合敲低显著增加了锯齿状-1 mRNA。此外，乙醇诱导 Jagged-1 和 ELAVL2 mRNA。在没有细胞凋亡的情况下，micro-RNAs的集体抑制与乙醇诱导细胞周期和神经上皮成熟一致。这些数据确定了micro-RNA作为表观遗传中介的作用，它允许致畸剂塑造复杂、不同的发育过程，并进一步证明协调调节的miRNA表现出功能协同作用和相互拮抗作用。

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