Zhang Ao, Desmazieres Anne, Zonta Barbara, Melrose Shona, Campbell Graham, Mahad Don, Li Qiushi, Sherman Diane L, Reynolds Richard, Brophy Peter J
Centre for Neuroregeneration, The Medical School, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom, and.
Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom.
J Neurosci. 2015 Feb 4;35(5):2246-54. doi: 10.1523/JNEUROSCI.3552-14.2015.
Rapid nerve conduction in myelinated nerves requires the clustering of voltage-gated sodium channels at nodes of Ranvier. The Neurofascin (Nfasc) gene has a unique role in node formation because it encodes glial and neuronal isoforms of neurofascin (Nfasc155 and Nfasc186, respectively) with key functions in assembling the nodal macromolecular complex. A third neurofascin, Nfasc140, has also been described; however, neither the cellular origin nor function of this isoform was known. Here we show that Nfasc140 is a neuronal protein strongly expressed during mouse embryonic development. Expression of Nfasc140 persists but declines during the initial stages of node formation, in contrast to Nfasc155 and Nfasc186, which increase. Nevertheless, Nfasc140, like Nfasc186, can cluster voltage-gated sodium channels (Nav) at the developing node of Ranvier and can restore electrophysiological function independently of Nfasc155 and Nfasc186. This suggests that Nfasc140 complements the function of Nfasc155 and Nfasc186 in initial stages of the assembly and stabilization of the nodal complex. Further, Nfasc140 is reexpressed in demyelinated white matter lesions of postmortem brain tissue from human subjects with multiple sclerosis. This expands the critical role of the Nfasc gene in the function of myelinated axons and reveals further redundancy in the mechanisms required for the formation of this crucial structure in the vertebrate nervous system.
有髓神经纤维中的快速神经传导需要电压门控钠通道在郎飞结处聚集。神经束蛋白（Neurofascin，Nfasc）基因在结的形成中具有独特作用，因为它编码神经束蛋白的神经胶质和神经元亚型（分别为Nfasc155和Nfasc186），在组装节点大分子复合物中具有关键功能。还描述了第三种神经束蛋白Nfasc140；然而，这种亚型的细胞起源和功能均未知。在这里，我们表明Nfasc140是一种在小鼠胚胎发育过程中强烈表达的神经元蛋白。与Nfasc155和Nfasc186增加的情况相反，Nfasc140的表达在结形成的初始阶段持续存在但下降。尽管如此，与Nfasc186一样，Nfasc140可以在发育中的郎飞结处聚集电压门控钠通道（Nav），并且可以独立于Nfasc155和Nfasc186恢复电生理功能。这表明Nfasc140在节点复合物组装和稳定的初始阶段补充了Nfasc155和Nfasc186的功能。此外，Nfasc140在患有多发性硬化症的人类受试者死后脑组织的脱髓鞘白质病变中重新表达。这扩展了Nfasc基因在有髓轴突功能中的关键作用，并揭示了脊椎动物神经系统中形成这一关键结构所需机制的进一步冗余性。
