Neurofascin 140 Is an Embryonic Neuronal Neurofascin Isoform That Promotes the Assembly of the Node of Ranvier
Neurofascin 140 Is an Embryonic Neuronal Neurofascin Isoform That Promotes the Assembly of the Node of Ranvier
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DOI：
10.1523/jneurosci.3552-14.2015
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发表时间：
2015-02-04
影响因子：
5.3
通讯作者：
Brophy, Peter J.
中科院分区：
文献类型：
--
作者：
Zhang, Ao;Desmazieres, Anne;Brophy, Peter J.
有髓神经中的快速神经传导需要电压门控钠通道在朗飞结处聚集。神经成膜蛋白 (Nfasc) 基因在节点形成中具有独特的作用，因为它编码神经成膜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。第三种神经成束蛋白 Nfasc140 也已被描述；然而，该异构体的细胞起源和功能均未知。在这里，我们证明 Nfasc140 是一种在小鼠胚胎发育过程中强烈表达的神经元蛋白。 Nfasc140 的表达持续存在，但在节点形成的初始阶段下降，而 Nfasc155 和 Nfasc186 的表达则增加。尽管如此，Nfasc140与Nfasc186一样，可以在Ranvier发育节点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 在节点复合体组装和稳定的初始阶段补充了 Nfasc155 和 Nfasc186 的功能。此外，Nfasc140 在多发性硬化症人类受试者死后脑组织的脱髓鞘白质病变中重新表达。这扩大了 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这一关键结构形成所需机制的进一步冗余。
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.