Precise Spatiotemporal Control of Nodal Na+ Channel Clustering by Bone Morphogenetic Protein-1/Tolloid-like Proteinases.

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.