The actin-severing protein cofilin is downstream of neuregulin signaling and is essential for Schwann cell myelination.
The actin-severing protein cofilin is downstream of neuregulin signaling and is essential for Schwann cell myelination.
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DOI：
10.1523/jneurosci.6207-11.2012
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发表时间：
2012-04-11
期刊：
影响因子：
--
通讯作者：
Fernandez-Valle C
中科院分区：
文献类型：
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作者：
Sparrow N;Manetti ME;Bott M;Fabianac T;Petrilli A;Bates ML;Bunge MB;Lambert S;Fernandez-Valle C
髓鞘形成是一个复杂的过程，需要协调定向运动和增加神经胶质细胞的大小，以产生多层髓鞘。髓鞘形成过程中肌动蛋白动力学的调节知之甚少。然而，已知髓鞘厚度与轴突表面上表达的神经调节蛋白-1（NRG 1）的丰度相关。在这里，我们确定cofilin 1，肌动蛋白解聚和切断蛋白，作为NRG 1信号在大鼠雪旺细胞（SC）的下游目标。在分离的SC中，NRG 1促进cofilin 1及其上游调节因子LIM激酶（LIMK）和Slingshot-1磷酸酶（SSH 1）的去磷酸化，导致cofilin 1活化和募集到质膜的前缘。这些变化与快速膜扩张产生35-50%的SC大小增加30分钟内。Cofilin 1缺陷的SC增加ErbB 2，ERK，粘着斑激酶和桩蛋白的磷酸化响应NRG 1，但未能增加的大小可能是由于稳定异常长的粘着斑。与感觉神经元共培养的Cofilin 1缺陷的SC不形成髓鞘。超微结构分析表明，它们不能成功地分离或接合轴突，只形成斑片状基底层。在与神经元共培养48小时后，cofilin 1缺陷的SC在轴突上不对齐或伸长，并且通常与下面的基底形成粘附。这项研究确定了cofilin 1及其上游调控因子LIMK和SSH 1作为NRG 1信号通路的最终靶点，并证明了cofilin 1对于SC轴突接合和髓鞘形成所需的细胞骨架的动态变化是必要的。
Myelination is a complex process requiring coordination of directional motility and an increase in glial cell size to generate a multilamellar myelin sheath. Regulation of actin dynamics during myelination is poorly understood. However, it is known that myelin thickness is related to the abundance of neuregulin-1 (NRG1) expressed on the axon surface. Here we identify cofilin1, an actin depolymerizing and severing protein, as a downstream target of NRG1 signaling in rat Schwann cells (SCs). In isolated SCs, NRG1 promotes dephosphorylation of cofilin1 and its upstream regulators, LIM kinase (LIMK) and Slingshot-1 phosphatase (SSH1), leading to cofilin1 activation and recruitment to the leading edge of the plasma membrane. These changes are associated with rapid membrane expansion yielding a 35–50% increase in SC size within 30 min. Cofilin1-deficient SCs increase phosphorylation of ErbB2, ERK, focal adhesion kinase, and paxillin in response to NRG1, but fail to increase in size possibly due to stabilization of unusually long focal adhesions. Cofilin1-deficient SCs cocultured with sensory neurons do not myelinate. Ultrastructural analysis reveals that they unsuccessfully segregate or engage axons and form only patchy basal lamina. After 48 h of coculturing with neurons, cofilin1-deficient SCs do not align or elongate on axons and often form adhesions with the underlying substrate. This study identifies cofilin1 and its upstream regulators, LIMK and SSH1, as end targets of a NRG1 signaling pathway and demonstrates that cofilin1 is necessary for dynamic changes in the cytoskeleton needed for axon engagement and myelination by SCs.