Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B.
Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B.
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DOI：
10.1523/jneurosci.5225-09.2010
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发表时间：
2010-02-17
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影响因子：
--
通讯作者：
Peles E
中科院分区：
文献类型：
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作者：
Horresh I;Bar V;Kissil JL;Peles E
Caspr和Caspr 2调节Ranvier节点周围不同轴突结构域的形成。Caspr是在结旁连接处（PNJ）产生膜屏障所必需的，而Caspr 2则作为在结旁连接区（JXP）聚集Kv 1通道的膜支架。Caspr和Caspr 2都与蛋白4.1B相互作用，这可能将结旁和结旁旁粘附复合物连接到轴突细胞骨架。为了确定蛋白4.1B在Caspr蛋白功能中的作用，我们检查了缺乏其4.1结合序列（d4.1）的转基因Caspr和Caspr 2突变体分别在Caspr和Caspr 2缺失小鼠中恢复Kv 1通道聚类的能力。我们发现Caspr-d4.1定位于PNJ，并且能够将结旁粘附复合物组分contactin和NF 155募集到该位点。然而，在表达Caspr-d4.1的轴突中，Kv 1通道经常在旁阳极检测到，这表明Caspr与蛋白4.1B的相互作用对于在PNJ产生有效的膜屏障是必要的。我们还发现，Caspr 2-d4.1转基因并没有积累在JXP，即使它是针对轴突，表明与蛋白4.1B的相互作用是必需的Caspr 2和Kv 1通道的积累在arctaparanodal轴突膜。因此，我们发现Caspr 2和Kv 1通道在4.1B无效小鼠中不聚集在JXP处。因此，我们的研究结果强调了蛋白4.1B在外周有髓轴突组织中的功能重要性。
Caspr and Caspr2 regulate the formation of distinct axonal domains around the nodes of Ranvier. Caspr is required for the generation of a membrane barrier at the paranodal junction (PNJ), whereas Caspr2 serves as a membrane scaffold that clusters Kv1 channels at the juxtaparanodal region (JXP). Both Caspr and Caspr2 interact with protein 4.1B, which may link the paranodal and juxtaparanodal adhesion complexes to the axonal cytoskeleton. To determine the role of protein 4.1B in the function of Caspr proteins, we examined the ability of transgenic Caspr and Caspr2 mutants lacking their 4.1-binding sequence (d4.1) to restore Kv1 channel clustering in Caspr and Caspr2 null mice, respectively. We found that Caspr-d4.1 was localized to the PNJ and is able recruit the paranodal adhesion complex components contactin and NF155 to this site. Nevertheless, in axons expressing Caspr-d4.1, Kv1 channels were often detected at paranodes, suggesting that the interaction of Caspr with protein 4.1B is necessary for the generation of an efficient membrane barrier at the PNJ. We also found that the Caspr2-d4.1 transgene did not accumulate at the JXP, even though it was targeted to the axon, demonstrating that the interaction with protein 4.1B is required for the accumulation of Caspr2 and Kv1 channels at the juxtaparanodal axonal membrane. In accordance, we show that Caspr2 and Kv1 channels are not clustered at the JXP in 4.1B null mice. Our results thus underscore the functional importance of protein 4.1B in the organization of peripheral myelinated axons.