Nogo-A and Myelin-Associated Glycoprotein Mediate Neurite Growth Inhibition by Antagonistic Regulation of RhoA and Rac1
Nogo-A and Myelin-Associated Glycoprotein Mediate Neurite Growth Inhibition by Antagonistic Regulation of RhoA and Rac1
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DOI：
10.1523/jneurosci.22-23-10368.2002
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发表时间：
2002-12
期刊：
影响因子：
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通讯作者：
B. Niederöst;T. Oertle;J. Fritsche;R. McKinney;C. Bandtlow
中科院分区：
文献类型：
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作者：
B. Niederöst;T. Oertle;J. Fritsche;R. McKinney;C. Bandtlow
成年哺乳动物中枢神经系统的神经再生和结构可塑性能力有限。神经胶质源性抑制因子髓磷脂相关糖蛋白 (MAG) 和 Nogo-A 的存在被认为为延长神经纤维提供了一个不允许的环境。特别是，Nogo-A（一种主要由少突胶质细胞表达的整合膜蛋白）已被证明会在体外和体内损害神经突生长。结构功能分析表明，Nogo-A 蛋白至少包含两个活性结构域 NiG 和 Nogo-66，对神经突生长和细胞扩散具有不同的影响。我们现在提供的证据表明，这些抑制结构域通过对小 GTP 酶 RhoA 和 Rac1 的拮抗调节来介导其作用，从而导致 RhoA 的激活和 Rac1 的抑制。通过用 C3 转移酶或下游效应 Rho 激酶 ROCK 用 Y27632 灭活 RhoA，Nogo-A 片段和 MAG 对神经突生长和少突胶质细胞介导的生长锥塌陷的抑制作用被消除。此外，我们表明最近克隆的 Nogo-66 和 MAG 受体 NgR 对于 NiG 或 MAG 诱导的 RhoA 激活不是必需的。
The adult mammalian CNS has a limited capacity for nerve regeneration and structural plasticity. The presence of glia-derived inhibitory factors myelin-associated glycoprotein (MAG) and Nogo-A have been suggested to provide a nonpermissive environment for elongating nerve fibers. In particular, Nogo-A, an integral membrane protein predominantly expressed by oligodendrocytes, has been demonstrated to impair neurite growth in vitro and in vivo. Structure function analysis revealed that Nogo-A protein contains at least two active domains, NiG and Nogo-66, with diverse effects on neurite outgrowth and cell spreading. We now provide evidence that these inhibitory domains mediate their effects via an antagonistic regulation of the small GTPases RhoA and Rac1, resulting in activation of RhoA and suppression of Rac1. By inactivating RhoA with C3 transferase or the downstream effector Rho-kinase ROCK withY27632, the inhibitory effects of both Nogo-A fragments and MAG on neurite outgrowth and oligodendrocyte-mediated growth cone collapse were abolished. Furthermore, we show that the recently cloned receptor for Nogo-66 and MAG, NgR, is not necessary for either NiG- or MAG-induced RhoA activation.