Taylor Anna M, Saifetiarova Julia, Bhat Manzoor A
Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, School of Medicine, University of Texas Health Science Center San Antonio, TX, USA.
Front Cell Neurosci. 2017 Feb 3;11:11. doi: 10.3389/fncel.2017.00011. eCollection 2017.
Intricate molecular interactions between neurons and glial cells underlie the creation of unique domains that are essential for saltatory conduction of action potentials by myelinated axons. Previously, the cell surface adhesion molecule Neurofascin (Nfasc) has been shown to have a dual-role in the establishment of axonal domains from both the glial and neuronal interface. While the neuron-specific isoform of Neurofascin (NF186) is indispensable for clustering of voltage-gated sodium channels at nodes of Ranvier; the glial-specific isoform of Neurofascin (NF155) is required for myelinating glial cells to organize the paranodal domain. Although many studies have addressed the individual roles of NF155 and NF186 in assembling paranodes and nodes, respectively; critical questions about their roles in the maintenance and long-term health of the myelinated axons remain, which we aimed to address in these studies. Here using spatiotemporal ablation of Neurofascin in neurons alone or together with myelinating glia, we report that loss of NF186 individually from postnatal mice leads to progressive nodal destabilization and axonal degeneration. While individual ablation of paranodal NF155 does not disrupt nodes of Ranvier; loss of NF186 combined with NF155 causes more accelerated nodal destabilization than loss of NF186 alone, providing strong evidence regarding a supporting role for paranodes in nodal maintenance. In both cases of NF186 loss, myelinating axons show ultrastructural changes and degeneration. Our studies reveal that long-term maintenance of nodes and ultimately the health of axons is correlated with the stability of NF186 within the nodal complex and the presence of auxiliary paranodes.
神经元与神经胶质细胞之间复杂的分子相互作用构成了独特区域的形成基础，这些区域对于有髓轴突的动作电位跳跃传导至关重要。此前，细胞表面黏附分子神经束蛋白（Neurofascin，Nfasc）已被证明在从神经胶质和神经元界面建立轴突区域中具有双重作用。虽然神经束蛋白的神经元特异性异构体（NF186）对于电压门控钠通道在郎飞结处的聚集不可或缺；但神经束蛋白的神经胶质特异性异构体（NF155）是有髓神经胶质细胞组织旁结区域所必需的。尽管许多研究分别探讨了NF155和NF186在组装旁结和结中的各自作用；但关于它们在有髓轴突的维持和长期健康中的作用的关键问题仍然存在，我们旨在通过这些研究来解决。在这里，我们单独或与有髓神经胶质细胞一起对神经元中的神经束蛋白进行时空消融，报告称仅从出生后小鼠中单独缺失NF186会导致渐进性的结不稳定和轴突退化。虽然对旁结NF155进行单独消融不会破坏郎飞结；但NF186与NF155同时缺失比单独缺失NF186会导致更快速的结不稳定，这为旁结在结维持中的支持作用提供了有力证据。在NF186缺失的两种情况下，有髓轴突均显示出超微结构变化和退化。我们的研究表明，结的长期维持以及最终轴突的健康与结复合物中NF186的稳定性和辅助旁结的存在相关。
