Opposing actions of ethanol and nicotine on microRNAs are mediated by nicotinic acetylcholine receptors in fetal cerebral cortical-derived neural progenitor cells.
Opposing actions of ethanol and nicotine on microRNAs are mediated by nicotinic acetylcholine receptors in fetal cerebral cortical-derived neural progenitor cells.
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DOI：
10.1111/j.1530-0277.2012.01793.x
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Miranda RC
中科院分区：
文献类型：
--
作者：
Balaraman S;Winzer-Serhan UH;Miranda RC
酒精和尼古丁经常被滥用。然而，它们对胎儿神经发育的综合影响，特别是对胎儿神经干细胞（NSCs），在妊娠中期产生成人大脑的大多数神经元，知之甚少。我们以前的研究表明，乙醇通过抑制特定microRNAs（miRNAs）的表达，部分影响NSC的成熟。在此，我们在胎儿NSC中测试了乙醇和尼古丁共调节已知乙醇敏感性（miR-9、miR-21、miR-153和miR-335）、尼古丁敏感性miRNA（miR-140- 3 p）和烟碱乙酰胆碱受体（nAChR）亚基的mRNA的程度。此外，我们测试了这些效应依赖于nAChR的程度。孕12.5天的小鼠胎鼠大脑皮质衍生的神经球培养物暴露于乙醇，尼古丁和美加明，一种非竞争性nAChR拮抗剂，单独或组合，短（24小时）和长（5天）的时间，以模拟在体内神经发生期间的暴露。通过qRT-PCR评估miRNA、miRNA调节的转录物和nAChR亚基mRNA的水平。乙醇抑制已知乙醇敏感性miRNAs和miR-140- 3 p的表达，而吸烟者达到的尼古丁浓度诱导这些miRNAs的剂量相关性增加。尼古丁的作用被乙醇和美加明阻断。最后，乙醇降低了nAChR亚基mRNA的表达，并且与美加明一样，阻止了尼古丁相关的α4和β2 nAChR转录物的增加。乙醇和尼古丁对胎儿神经干细胞中致畸敏感的miRNAs产生相互拮抗的nAChR介导的作用。这些数据表明，同时暴露于乙醇和尼古丁会破坏对NSC成熟至关重要的miRNA调控网络。
Ethanol and nicotine are often co-abused. However, their combined effects on fetal neural development, particularly on fetal neural stem cells (NSCs), which generate most neurons of the adult brain during the second trimester of pregnancy, are poorly understood. We previously showed that ethanol influenced NSC maturation in part, by suppressing expression of specific microRNAs (miRNAs). Here, we tested in fetal NSCs, the extent to which ethanol and nicotine co-regulated known ethanol-sensitive (miR-9, miR-21, miR-153 and miR-335), a nicotine-sensitive miRNA (miR-140-3p), and mRNAs for nicotinic acetylcholine receptor (nAChR) subunits. Additionally, we tested the extent to which these effects were nAChR dependent. Gestational day 12.5 mouse fetal murine cerebral cortical-derived neurosphere cultures were exposed to ethanol, nicotine and mecamylamine, a noncompetitive nAChR antagonist, individually or in combination, for short (24 hour) and long (five day) periods, to mimic exposure during the in vivo period of neurogenesis. Levels of miRNAs, miRNA-regulated transcripts and nAChR subunit mRNAs were assessed by qRT-PCR. Ethanol suppressed expression of known ethanol-sensitive miRNAs and miR-140-3p, while nicotine at concentrations attained by cigarette smokers, induced a dose-related increase in these miRNAs. Nicotine’s effect was blocked by ethanol and by mecamylamine. Finally, ethanol decreased expression of nAChR subunit mRNAs and, like mecamylamine, prevented the nicotine associated increase in α4 and β2 nAChR transcripts. Ethanol and nicotine exert mutually antagonistic, nAChR-mediated effects on teratogen-sensitive miRNAs in fetal NSCs. These data suggest that concurrent exposure to ethanol and nicotine disrupts miRNA regulatory networks that are important for NSC maturation.
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影响因子：
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作者：
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通讯作者：
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DOI：
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