Transmembrane scaffolding proteins in the formation and stability of nodes of Ranvier

The function of myelinated fibers depends on the clustering of sodium channels at nodes of Ranvier, the integrity of the myelin sheath, and the existence of tight axoglial junctions at paranodes, on either sides of the nodes. While the ultrastructure of these regions has been known for several decades, recent progress has been accomplished in the identification of proteins essential for their organization, which depends on the interplay between axons and myelinating glial cells. Evolutionary conserved intercellular multimolecular complexes comprising proteins of the Neurexin IV/Caspr/paranodin (NCP) family and of the immunoglobulin-like cell adhesion molecules superfamily, are essential components for the axoglial contacts at the level of paranodes and juxtaparanodes. These complexes are able to interact with cytoplasmic proteins of the band 4.1 family, providing possible links to the axonal cytoskeleton. While the identification of these proteins represents a significant progress for understanding axoglial contacts, they also raise exciting questions concerning the molecular organization of these contacts and the mechanisms of their local enrichment.