Contacts cellulaires des fibres myélinisées du système nerveux périphérique Cellular contacts in myelinated fibers of the peripheral nervous system

Résumé

L’architecture et la fonction des fibres myélinisées sont dépendantes de l’établissement de contacts cellulaires finement réglés entre les membranes d’une même cellule gliale myélinisante, entre l’axone et les cellules gliales, et entre les cellules gliales et la matrice extracellulaire. Des composants protéiques majeurs de l’ensemble de ces contacts ont été identifiés ces dernières années. Des progrès importants ont notamment été faits dans l’identification de complexes moléculaires impliqués dans les contacts axo-gliaux au niveau des noeuds de Ranvier. Le rôle capital de certains composants des contacts dans le maintien de l’intégrité structurale et fonctionnelle des fibres a été démontré par la production de modèles murins. Dans certains cas, des mutations des gènes correspondants ont été identifiées chez des patients atteints de neuropathies périphériques telles que les maladies de Charcot-Marie-Tooth (CMT).

Summary

Myelination allows the fast propagation of action potentials at a low energetic cost. It provides an insulating myelin sheath regularly interrupted at nodes of Ranvier where voltage-gated Na⁺ channels are concentrated. In the peripheral nervous system, the normal function of myelinated fibers requires the formation of highly differentiated and organized contacts between the myelinating Schwann cells, the axons and the extracellular matrix. Some of the major molecular complexes that underlie these contacts have been identified. Compact myelin which forms the bulk of the myelin sheath results from the fusion of the Schwann cell membranes through the proteins P0, PMP22 and MBP. The basal lamina of myelinating Schwann cells contains laminin-2 which associates with the glial complex dystroglycan/DPR2/L-periaxin. Non compact myelin, found in paranodal loops, periaxonal and abaxonal regions, and Schmidt-Lanterman incisures, presents reflexive adherens junctions, tight junctions and gap junctions, which contain cadherins, claudins and connexins, repectively. Axo-glial contacts determine the formation of distinct domains on the axon, the node, the paranode, and the juxtaparanode. At the paranodes, the glial membrane is tightly attached to the axolemma by septate-like junctions. Paranodal and juxtaparanodal axoglial complexes comprise an axonal transmembrane protein of the NCP family associated in cis and in trans with cell adhesion molecules of the immunoglobulin superfamily (IgSF-CAM). At nodes, axonal complexes are composed of Na⁺ channels and IgSF-CAMs. Schwann cell microvilli, which loosely cover the node, contain ERM proteins and the proteoglycans syndecan-3 and -4. The fundamental role of the cellular contacts in the normal function of myelinated fibers has been supported by rodent models and the detection of genetic alterations in patients with peripheral demyelinating neuropathies such as Charcot-Marie-Tooth diseases. Understanding more precisely their molecular basis now appears essential as a requisite step to further examine their involvement in the pathogenesis of peripheral neuropathies in general.