In vivo deletion of immunoglobulin domains 5 and 6 in neurofascin (Nfasc) reveals domain-specific requirements in myelinated axons.
In vivo deletion of immunoglobulin domains 5 and 6 in neurofascin (Nfasc) reveals domain-specific requirements in myelinated axons.
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DOI：
10.1523/jneurosci.5951-09.2010
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发表时间：
2010-04-07
期刊：
影响因子：
--
通讯作者：
Bhat MA
中科院分区：
文献类型：
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作者：
Thaxton C;Pillai AM;Pribisko AL;Labasque M;Dupree JL;Faivre-Sarrailh C;Bhat MA
神经旁轴胶质连接的形成对神经冲动的快速有效传播至关重要。编码关键副神经节蛋白Caspr、contactn （Cont）和神经束蛋白（NfascNF155）的髓鞘胶质特异性异构体基因的遗传消损导致副神经节轴-胶质连接的破坏、离子通道分离的丧失和神经传导的受损，但调节它们相互作用的机制仍然难以捉摸。在这里，我们报告了NfascNF155免疫球蛋白（Ig）结构域5和6的缺失在小鼠表型中完全消融了NfascNF155。突变小鼠缺乏旁结分离连接，导致Caspr和Cont从偏执症扩散，并使旁结旁钾通道向淋巴结重新分布。虽然Ig5-6对NfascNF155的功能至关重要，但我们发现Ig5-6对于NfascNF186的节点功能是必不可少的。此外，使用Ig5-6缺失构建体的体外结合实验揭示了它们对NfascNF155与Cont关联的重要性。这些发现提供了第一个分子证据，证明了在体内控制副神经节三方复合物关联的结构域特异性要求。我们的研究进一步强调，体内结构/功能分析对于确定在轴突结构域组织过程中差异调节神经束蛋白功能的独特蛋白质/蛋白质相互作用是必要的。
The formation of paranodal axo-glial junctions is critical for the rapid and efficient propagation of nerve impulses. Genetic ablation of genes encoding the critical paranodal proteins Caspr, contactin (Cont), and the myelinating glia-specific isoform of Neurofascin (NfascNF155) results in the disruption of the paranodal axo-glial junctions, loss of ion channel segregation, and impaired nerve conduction, but the mechanisms regulating their interactions remains elusive. Here, we report that loss of immunoglobulin (Ig) domains 5 and 6 in NfascNF155 in mice phenocopies complete ablation of NfascNF155. The mutant mice lack paranodal septate junctions, resulting in the diffusion of Caspr and Cont from the paranodes, and redistribution of the juxtaparanodal potassium channels towards the nodes. While critical for NfascNF155 function, we find that Ig5-6 are dispensable for nodal NfascNF186 function. Moreover, in vitro binding assays using Ig5-6 deletion constructs reveal their importance for the association of NfascNF155 with Cont. These findings provide the first molecular evidence demonstrating domain specific requirements controlling the association of the paranodal tripartite complex in vivo. Our studies further emphasize that in vivo structure/function analysis is necessary to define the unique protein/protein interactions that differentially regulate the functions of Neurofascins during axonal domain organization.