Embryonic exposure to ethanol disturbs regulation of mitotic spindle orientation via GABAA receptors in neural progenitors in ventricular zone of developing neocortex
Embryonic exposure to ethanol disturbs regulation of mitotic spindle orientation via GABAA receptors in neural progenitors in ventricular zone of developing neocortex
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DOI：
10.1016/j.neulet.2010.01.071
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发表时间：
2010-03-19
影响因子：
2.5
通讯作者：
Fukui, Yoshihiro
中科院分区：
文献类型：
--
作者：
Tochitani, Shiro;Sakata-Haga, Hiromi;Fukui, Yoshihiro
发育中的新皮质的脑室区中的神经祖细胞基于其有丝分裂纺锤体方向而平行或垂直于脑室表面分裂。它已被证明，卵裂平面的方向是发育调节，并在神经祖细胞的细胞命运决定或在新皮质发育过程中的增殖脑室区的维护中起着至关重要的作用。我们测试，如果胎儿暴露于乙醇，最广泛使用的精神活性剂和一个强大的致畸剂，可能会导致畸形的中枢神经系统，改变有丝分裂方向的神经祖细胞在发育中的新皮层的脑室区的顶面。胎仔在E10.5和11.5暴露于乙醇增加了E12.5平行于心室表面的水平卵裂平面的发生频率。在给予乙醇之前给予印防己毒素（一种GABA（A）受体拮抗剂）可消除乙醇的作用，水平分裂频率与对照水平相似，尽管印防己毒素本身对分裂平面方向没有任何影响。苯巴比妥，一种GABA（A）受体激动剂，诱导水平分裂的程度与乙醇给药诱导的相似。（+）MK801是神经细胞中乙醇的另一个主要靶点NMDA受体的拮抗剂，不影响分裂祖细胞的分裂平面。这些结果表明，胎儿乙醇暴露通过增强GABA（A）受体的功能诱导了新皮层脑室区神经祖细胞卵裂面方向的改变。(C)2010爱思唯尔爱尔兰有限公司版权所有。
Neural progenitors in the ventricular zone of the developing neocortex divide oriented either parallel or perpendicular to the ventricular surface based on their mitotic spindle orientation. It has been shown that the cleavage plane orientation is developmentally regulated and plays a crucial role in cell fate determination of neural progenitors or the maintenance of the proliferative ventricular zone during neocortical development. We tested if fetal exposure to ethanol, the most widely used psychoactive agent and a potent teratogen that may cause malformation in the central nervous system, alters mitotic cleavage orientation of the neural progenitors at the apical surface of the ventricular zone in the developing neocortex. Fetal exposure to ethanol on E10.5 and 11.5 increased the occurrence frequency of a horizontal cleavage plane that is parallel to the ventricular surface on E 12.5. Administration of picrotoxin, a GABA(A) receptor antagonist, prior to ethanol administration canceled the effect of ethanol with the frequency of horizontal division similar to the control level, although picrotoxin itself did not show any effect on cleavage plane orientation. Phenobarbital, a GABA(A) receptor agonist, induced horizontal cleavage to an extent similar to that induced by ethanol administration. (+)MK801, an antagonist of NMDA receptor that is another major target of ethanol in neural cells, did not affect the cleavage plane of dividing progenitors. These results suggest that fetal ethanol exposure induced alterations in the cleavage plane orientation of neural progenitors in the ventricular zone of the neocortex via the enhancement of the function of GABA(A) receptors. (C) 2010 Elsevier Ireland Ltd. All rights reserved.