Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly
Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly
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DOI：
10.1073/pnas.0603533103
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发表时间：
2006-10-31
影响因子：
11.1
通讯作者：
Zheng, Yi
中科院分区：
文献类型：
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作者：
Chen, Lei;Liao, Guanghong;Zheng, Yi
哺乳动物大脑的端脑神经上皮(NE)具有顶基两极，其特征是神经前体细胞定位于顶端/脑室表面，并附着在顶端/脑室表面的连接，以及放射状胶质/前体纤维向软膜/基底面上升。建立NE这种尖基两极的信号通路尚不完全清楚，但Rho家族GTP酶CDc42可能起着关键作用，因为它控制着许多物种中基于钙粘附素的细胞间连接和细胞极性。在这里，我们通过一种有条件的基因打靶策略来验证这一假设，方法是使用FOXG1-Cre系来删除小鼠胚胎端脑神经前体细胞中的CDC42。我们发现，CDC42缺失取消了PAR6、aPKC、E-cadherin、β-catenin和Numb蛋白在NE中的顶端定位，并严重损害了Nestin阳性神经纤维的伸展。因此，神经前体散布在NE的整个深度，而缺乏Cdc42的端脑不能膨胀或分离成两个大脑半球，导致完整的前脑。然而，Cdc42缺失既不影响Sonic Hedgehog的中线表达，也不影响端脑的背腹模式。综上所述，这些结果表明，CDC42在建立端脑NE的顶底极性中起着重要作用，而端脑NE是大脑半球扩张和分叉所必需的。
The telencephalic neuroepithelium (NE) of mammalian brain has an apical-basal polarity that is marked by the positioning of neural progenitors and adherens junctions on the apical/ventricular surface and the ascending of radial glia/progenitor fibers toward the pial/basal surface. The signaling pathway that establishes this apical-basal polarity of NE is not completely understood, but the Rho-family GTPase Cdc42 may play a critical role because it controls cadherin-based intercellular junctions and cell polarity in many species. Here, we tested this hypothesis by a conditional gene-targeting strategy by using the Foxg1-Cre line to delete Cdc42 in the telencephalic neural progenitors in mouse embryos. We found that Cdc42-deletion abolishes the apical localization of PAR6, aPKC, E-cadherin, beta-catenin, and Numb proteins in the NE, and severely impairs the extension of nestin-positive radial fibers. Consequently, neural progenitors were scattered throughout the entire depth of the NE, and the Cdc42-deficient telencephalon failed to bulge or separate into two cerebral hemispheres, resulting in holoprosencephaly. However, neither the midline expression of Sonic hedgehog nor the dorso-ventral patterning of the telencephalon was affected by Cdc42-deletion. Taken together, these results indicate that Cdc42 has an essential role in establishing the apical-basal polarity of the telencephalic NE, which is needed for the expansion and bifurcation of cerebral hemispheres.