Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, Florida 32827, USA.
J Neurosci. 2012 Apr 11;32(15):5284-97. doi: 10.1523/JNEUROSCI.6207-11.2012.
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.
髓鞘形成是一个复杂的过程，需要协调定向运动和神经胶质细胞的增大，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表达的神经调节蛋白 1（NRG1）的丰度有关。在这里，我们确定了丝切蛋白 1（cofilin1），一种肌动蛋白解聚和切割蛋白，是大鼠雪旺细胞（SCs）中 NRG1 信号的下游靶标。在分离的 SC 中，NRG1 促进 cofilin1 及其上游调节剂 LIM 激酶（LIMK）和 Slingshot-1 磷酸酶（SSH1）的去磷酸化，导致 cofilin1 激活并募集到质膜前缘。这些变化与快速的膜扩张有关，导致 SC 大小在 30 分钟内增加 35-50%。NRG1 刺激下，cofilin1 缺陷型 SC 中 ErbB2、ERK、粘着斑激酶和桩蛋白的磷酸化增加，但由于异常长的粘着斑稳定，细胞大小无法增加。与感觉神经元共培养的 cofilin1 缺陷型 SC 不能髓鞘形成。超微结构分析显示，它们不能成功地分隔或接触轴突，只能形成斑驳的基底层。与神经元共培养 48 小时后，cofilin1 缺陷型 SC 不能在轴突上排列或伸长，并且经常与基底膜下的基质形成粘连。这项研究确定了丝切蛋白 1 及其上游调节剂 LIMK 和 SSH1 作为 NRG1 信号通路的终靶标，并表明 cofilin1 是 SC 接触和髓鞘形成所需的细胞骨架动态变化所必需的。
