Myelin-associated inhibitors regulate cofilin phosphorylation and neuronal inhibition through LIM kinase and slingshot phosphatase
Myelin-associated inhibitors regulate cofilin phosphorylation and neuronal inhibition through LIM kinase and slingshot phosphatase
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DOI：
10.1523/jneurosci.2806-05.2006
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发表时间：
2006-01-18
影响因子：
5.3
通讯作者：
Fournier, AE
中科院分区：
文献类型：
--
作者：
Hsieh, SHK;Ferraro, GB;Fournier, AE
髓鞘相关抑制剂（迈斯）通过神经元上的三部分受体复合物发出信号，以限制CNS中的轴突再生。抑制作用最终集中在细胞骨架上，以介导生长锥塌陷和神经突生长抑制。Rho GT3及其下游效应物Rho激酶是应答迈斯的关键信号中间体;然而，Rho与肌动蛋白细胞骨架之间的联系尚未完全确定。我们发现Nogo-66是Nogo-A的有效抑制片段，通过LIM（LIM是三种基因产物Lin-11、Isl-1和Mec-3的首字母缩写）激酶和Slingshot（SSH）磷酸酶来调节肌动蛋白解聚因子cofilin的磷酸化谱。LIMK 1激活和随后的cofilin磷酸化的阻断可以避免鸡背根神经节神经元中的髓鞘依赖性抑制，这表明cofilin的磷酸化和失活对于神经元抑制反应至关重要。SSH 1磷酸酶的后续激活介导了cofilin去磷酸化和再激活。SSH 1的过表达不能模拟髓鞘的轴突生长抑制作用，这表明在MAI抑制中的替代作用。我们推测，SSH介导的持续性cofilin激活可能是负责维持抑制神经元表型响应髓鞘抑制剂。
Myelin-associated inhibitors (MAIs) signal through a tripartate receptor complex on neurons to limit axon regeneration in the CNS. Inhibitory influences ultimately converge on the cytoskeleton to mediate growth cone collapse and neurite outgrowth inhibition. Rho GTPase and its downstream effector Rho kinase are key signaling intermediates in response to MAIs; however, the links between Rho and the actin cytoskeleton have not been fully defined. We found that Nogo-66, a potent inhibitory fragment of Nogo-A, signals through LIM ( LIM is an acronym of the three gene products Lin-11, Isl-1, and Mec-3) kinase and Slingshot (SSH) phosphatase to regulate the phosphorylation profile of the actin depolymerization factor cofilin. Blockade of LIMK1 activation and subsequent cofilin phosphorylation circumvents myelin-dependent inhibition in chick dorsal root ganglion neurons, suggesting that phosphorylation and inactivation of cofilin is critical for neuronal inhibitory responses. Subsequent activation of SSH1 phosphatase mediates cofilin dephosphorylation and reactivation. Overexpression of SSH1 does not mimic the neurite outgrowth inhibitory effects of myelin, suggesting an alternative role in MAI inhibition. We speculate that SSH-mediated persistent cofilin activation may be responsible for maintaining an inhibited neuronal phenotype in response to myelin inhibitors.