GSK3β Regulates Myelin-Dependent Axon Outgrowth Inhibition through CRMP4
GSK3β Regulates Myelin-Dependent Axon Outgrowth Inhibition through CRMP4
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DOI：
10.1523/jneurosci.6154-09.2010
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发表时间：
2010-04-21
影响因子：
5.3
通讯作者：
Fournier, Alyson E.
中科院分区：
文献类型：
--
作者：
Alabed, Yazan Z.;Pool, Madeline;Fournier, Alyson E.
髓鞘相关抑制剂（MAI）导致CNS的再生失败。 MAI轴突修复的细胞内信号通路在很大程度上未知。在这里，我们报告了激酶GSK3ββ直接被MAI磷酸化和灭活，因此调节对髓磷脂依赖性抑制至关重要的蛋白质蛋白质相互作用。抑制GSK3ββ模拟髓磷脂的神经突生长抑制作用。 GSK3β抑制剂和髓磷脂的抑制作用并不是添加剂，表明GSK3β是MAI的主要效应子。与此相一致，GSK3β的过表达减轻了髓磷脂的抑制作用。 MAI依赖性磷酸化和GSK3βββ的失活调节CRMP4的磷酸化，CRMP4是髓磷脂抑制的胞质调节剂，及其与RhoA复合的能力。引入CRMP4拮抗剂会减弱GSK3β抑制剂的神经突生长抑制特性。我们描述了响应抑制性配体的GSK3β灭活的第一个例子，并将GSK3β抑制的神经突生长抑制作用直接与CRMP4联系起来。这些发现增加了GSK3β抑制作用在创伤之类的创伤之后无法有效促进长途中枢神经系统再生的可能性。
Myelin-associated inhibitors (MAIs) contribute to failed regeneration in the CNS. The intracellular signaling pathways through which MAIs block axonal repair remain largely unknown. Here, we report that the kinase GSK3 beta is directly phosphorylated and inactivated by MAIs, consequently regulating protein-protein interactions that are critical for myelin-dependent inhibition. Inhibition of GSK3 beta mimics the neurite outgrowth inhibitory effect of myelin. The inhibitory effects of GSK3 beta inhibitors and myelin are not additive indicating that GSK3 beta is a major effector of MAIs. Consistent with this, overexpression of GSK3 beta attenuates myelin inhibition. MAI-dependent phosphorylation and inactivation of GSK3 beta regulate phosphorylation of CRMP4, a cytosolic regulator of myelin inhibition, and its ability to complex with RhoA. Introduction of a CRMP4 antagonist attenuates the neurite outgrowth inhibitory properties of GSK3 beta inhibitors. We describe the first example of GSK3 beta inactivation in response to inhibitory ligands and link the neurite outgrowth inhibitory effects of GSK3 beta inhibition directly to CRMP4. These findings raise the possibility that GSK3 beta inhibition will not effectively promote long-distance CNS regeneration following trauma such as spinal cord injury.