The cytoskeletal adaptor protein band 4.1B is required for the maintenance of paranodal axoglial septate junctions in myelinated axons.
The cytoskeletal adaptor protein band 4.1B is required for the maintenance of paranodal axoglial septate junctions in myelinated axons.
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DOI：
10.1523/jneurosci.1015-11.2011
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发表时间：
2011-06-01
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：
Buttermore ED;Dupree JL;Cheng J;An X;Tessarollo L;Bhat MA
精确定位和维持有髓轴突中的轴突结构域对于跳跃式传导是必不可少的。Caspr和Caspr 2位于结旁和结旁区，含有细胞骨架衔接蛋白4.1B的结合位点。4.1B在轴突结构域的组织和维持中的确切作用尚不清楚。在这里，我们报告4.1B无效小鼠的产生和表征。我们发现，早在出生后第30天，PNS中4.1B的丢失导致Caspr在旁结处的错误定位和旁结轴胶质细胞分隔连接（AGSJS）的不稳定。在CNS中，Caspr定位逐渐被破坏，超微结构分析显示完全没有AGSJ的结旁区域，轴膜与髓磷脂环分离，并且环从轴膜脱落。最重要的是，我们对先前产生的4.1B突变体的表型分析表明，即使在一年后，PNS中的Caspr定位也没有受到影响; 4.1R既没有表达，也没有在副阳极富集。此外，这些4.1B突变体的超微结构分析显示CNS AGSJS在约一年时不稳定。我们还发现4.1B基因座在PNS和CNS中差异表达，并在PNS中产生多种剪接异构体，这表明4.1B在PNS和CNS中可能具有不同的功能。总之，我们的研究提供了直接的证据表明，4.1B在结旁AGSJS和轴突细胞骨架之间的相互作用中起着关键作用，并且4.1B对于有髓鞘轴突中轴突结构域的长期维持至关重要。
Precise targeting and maintenance of axonal domains in myelinated axons is essential for saltatory conduction. Caspr and Caspr2, which localize at paranodal and juxtaparanodal domains, contain binding sites for the cytoskeletal adaptor protein 4.1B. The exact role of 4.1B in the organization and maintenance of axonal domains is still not clear. Here we report the generation and characterization of 4.1B null mice. We show that loss of 4.1B in the PNS results in mislocalization of Caspr at paranodes and destabilization of paranodal axo-glial septate junctions (AGSJs) as early as postnatal day 30. In the CNS, Caspr localization is progressively disrupted and ultrastructural analysis showed paranodal regions that were completely devoid of AGSJs, with axolemma separated from the myelin loops, and loops coming off the axolemma. Most importantly, our phenotypic analysis of previously generated 4.1B mutants, used in, showed that Caspr localization was not affected in the PNS, even after one year; and 4.1R was neither expressed, nor enriched at the paranodes. Furthermore, ultrastructural analysis of these 4.1B mutants showed destabilization of CNS AGSJs at about one year. We also discovered that the 4.1B locus is differentially expressed in the PNS and CNS, and generates multiple splice isoforms in the PNS, suggesting 4.1B may function differently in the PNS versus CNS. Together, our studies provide direct evidence that 4.1B plays a pivotal role in interactions between the paranodal AGSJs and axonal cytoskeleton, and that 4.1B is critically required for long-term maintenance of axonal domains in myelinated axons.