The Small GTPase RhoA Is Required to Maintain Spinal Cord Neuroepithelium Organization and the Neural Stem Cell Pool
The Small GTPase RhoA Is Required to Maintain Spinal Cord Neuroepithelium Organization and the Neural Stem Cell Pool
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DOI：
10.1523/jneurosci.4807-10.2011
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发表时间：
2011-03-30
影响因子：
5.3
通讯作者：
Relvas, Joao B.
中科院分区：
文献类型：
--
作者：
Herzog, Dominik;Loetscher, Pirmin;Relvas, Joao B.
粘附连接（AJs）的调节对于CNS发育过程中的多个事件至关重要，包括神经上皮的形成和维持。我们已经解决了小GTdR RhoA在小鼠神经系统发育中的作用，使用组织特异性条件基因消融。我们发现，在脊髓神经上皮细胞，RhoA是必不可少的本地化N-钙粘蛋白和β-连环蛋白的AJs和维持顶-基底极性的神经祖细胞。RhoA的消融导致AJs的丢失和神经上皮内细胞组织的严重异常，包括神经上皮细胞增殖减少和过早的细胞周期退出，神经干细胞池大小减少，以及神经上皮细胞浸润到心室腔中。我们还表明，在没有RhoA的情况下，其效应，哺乳动物透明相关的formin 1（mDia 1），不本地化顶端AJs，它可能通过促进局部肌动蛋白聚合和微管组织稳定细胞内粘附。此外，在神经干细胞/祖细胞中表达显性阴性形式的mDia 1导致与RhoA条件性敲除的表型相似的表型，即AJs和顶端极性的丧失。总之，我们的数据表明，RhoA信号是必要的AJ调节和维护哺乳动物神经上皮组织防止早熟细胞周期退出和分化。
he regulation of adherens junctions (AJs) is critical for multiple events during CNS development, including the formation and maintenance of the neuroepithelium. We have addressed the role of the small GTPase RhoA in the developing mouse nervous system using tissue-specific conditional gene ablation. We show that, in the spinal cord neuroepithelium, RhoA is essential to localize N-cadherin and beta-catenin to AJs and maintain apical-basal polarity of neural progenitor cells. Ablation of RhoA caused the loss of AJs and severe abnormalities in the organization of cells within the neuroepithelium, including decreased neuroepithelial cell proliferation and premature cell-cycle exit, reduction of the neural stem cell pool size, and the infiltration of neuroepithelial cells into the lumen of the ventricle. We also show that, in the absence of RhoA, its effector, mammalian diaphanous-related formin1 (mDia1), does not localize to apical AJs in which it likely stabilizes intracellular adhesion by promoting local actin polymerization and microtubule organization. Furthermore, expressing a dominant-negative form of mDia1 in neural stem/progenitor cells results in a similar phenotype compared with that of the RhoA conditional knock-out, namely the loss of AJs and apical polarity. Together, our data show that RhoA signaling is necessary for AJ regulation and for the maintenance of mammalian neuroepithelium organization preventing precocious cell-cycle exit and differentiation.