During development of the peripheral nervous system (PNS), Schwann-cell-secreted gliomedin induces the clustering of Na⁺ channels at the edges of each myelin segment to form nodes of Ranvier. Here we show that bone morphogenetic protein-1 (BMP1)/Tolloid (TLD)-like proteinases confine Na⁺ channel clustering to these sites by negatively regulating the activity of gliomedin. Eliminating the Bmp1/TLD cleavage site in gliomedin or treating myelinating cultures with a Bmp1/TLD inhibitor results in the formation of numerous ectopic Na⁺ channel clusters along axons that are devoid of myelin segments. Furthermore, genetic deletion of Bmp1 and Tll1 genes in mice using a Schwann-cell-specific Cre causes ectopic clustering of nodal proteins, premature formation of heminodes around early ensheathing Schwann cells, and altered nerve conduction during development. Our results demonstrate that by inactivating gliomedin, Bmp1/TLD functions as an additional regulatory mechanism to ensure the correct spatial and temporal assembly of PNS nodes of Ranvier.

在周围神经系统 (PNS) 的发育过程中，雪旺细胞分泌的 gliomedin 诱导每个髓鞘节段边缘的 Na ⁺通道聚集，形成 Ranvier 节点。在这里，我们显示骨形态发生蛋白-1 (BMP1)/Tolloid (TLD) 样蛋白酶通过负调节 gliomedin 的活性将 Na ^{+通道聚集到这些位点。}消除 gliomedin 中的 Bmp1/TLD 切割位点或用 Bmp1/TLD 抑制剂处理髓鞘培养会导致沿轴突形成许多异位 Na ⁺通道簇，这些轴突没有髓鞘片段。此外，Bmp1和Tll1的遗传缺失使用雪旺细胞特异性 Cre 的小鼠基因会导致结节蛋白异位聚集，在早期鞘状雪旺细胞周围过早形成 heminodes，并在发育过程中改变神经传导。我们的研究结果表明，通过使 gliomedin 失活，Bmp1/TLD 作为一种额外的调节机制来确保 Ranvier 的 PNS 节点的正确空间和时间组装。