Myelination

Abstract

A series of interactions between axons and Schwann cells govern peripheral nerve development (Mirsky and Jessen, 1999). Axonally derived neuregulin-1 is required for the survival and proliferation of Schwann cell precursors, which, in turn, are required for the survival of neurons. As Schwann cell precursors develop into immature Schwann cells, they surround large bundles of axons and become polarized—the inside facing the axons, the outside depositing a basal lamina. Beginning at this time, and extending for many days thereafter, sheet-like Schwann processes infiltrate these axonal bundles, separating them into ever smaller bundles, and some axons are individually ensheathed (Webster, 1993). The promyelinating Schwann cells, the ones ensheathing axons in a 1:1 manner, subsequently form a myelin sheath within a few days. Unlike the Schwann cells that surround axonal bundles, promyelinating and myelinating Schwann cells are completely surrounded by a basal lamina. In this way, axons that are destined to be myelinated acquire the proper complement of Schwann cells, whereas nonmyelinated axons remain associated with cords of nonmyelinating Schwann cells. A role for the basal lamina in axonal ensheathment and myelination has long been suspected (Bunge, 1993). The genetic evidence is based on the analysis of dystrophic mice and humans with congenital muscular dystrophy (CMD);* both have mutations in the laminin 2 gene (Pegoraro et al., 1998; Xu et al., 1994), resulting in a lack of laminin-2 (the 2 1 1 isoform). Lama2/LAMA2 mutations cause muscular dystrophy because laminin-2 is a ligand for dystroglycan, an essential extracellular matrix receptor expressed by skeletal muscle cells. Although myopathy predominates the clinical picture, some CMD patients have abnormal nerve conduction velocities, indicating that myelination is affected, too. Schwann cells express dystroglycan and even several sarcoglycans (Imamura et al., 2000), but the molecular basis of the neuropathy in CMD patients is not known. The finding that the ventral roots of adult dystrophic mice contain bundles of unensheathed axons—the persistence of an embryonic phenotype—provides an important clue in this regard. Despite the known role of laminin-2 in myelination, its receptor and mechanism of action have not been previously elucidated. The report of Feltri et al. (2001) provides important insights into these issues. They conditionally deleted the gene encoding integrin 1, a component of laminin receptors, in immature Schwann cells ( 1 integrin was absent by E17.5), before the formation of promyelinating Schwann cells, and found that myelination is markedly delayed. This delay results from the failure of Schwann cells both to subdivide bundles of axons and to progress past the promyelinating stage. Furthermore, the cell membrane of “arrested” promyelinating Schwann cells frequently fails to appose the basal lamina and even retracts, leaving the axon unensheathed. The myelinated axons that do arise, albeit belatedly, appear normal. These anatomical abnormalities likely preclude saltatory conduction and lead to the development of a progressive peripheral neuropathy. Thus, immature Schwann cells require 1 integrin to properly segregate bundled axons during development, and promyelinating Schwann cells may require 1 integrin to adhere to their basal laminae and initiate the formation of a myelin sheath. The earlier observation that antibodies against 1 integrin interfere with myelination in vitro (Fernandez-Valle et al., 1994) is elegantly confirmed and extended. The findings of Feltri et al. (2001) suggest that the receptor for laminin-2 switches during development. As depicted in Fig. 1, immature and promyelinating Schwann cells express 6 1 integrin, whereas myelinating Schwann cells predominately express 6 4 integrin (Previtali et al., 2001). In epithelial cells, 6 4 integrin links the basal lamina to intermediate filaments via hemidesmosomes, whereas Schwann cells do not have hemidesmosomes. Thus, 6 4 may be linked to the actin cytoskeleton rather than to intermediate filaments. Although dystroglycan appears to be expressed on both promyelinating and myelinating Schwann cells, only the latter express a protein that interacts with dystroglycan, dystroglycan-related protein 2 (DRP2), as well as a protein that interacts with DRP2, periaxin (Sherman et al., 2001). Dystroglycan, DRP2, and periaxin form a macromolecular Address correspondence to S.S. Scherer, The University of Pennsylvania Medical Center, Room 460 Stemmler Hall, 36th Street and Hamilton Walk, Philadelphia, PA 19104-6077. Tel.: (215) 573-3198. Fax: (215) 573-4454. E-mail: sscherer@mail.med.upenn.edu

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@article{Scherer2002Myelination, title={Myelination}, author={Steven S . Scherer}, journal={The Journal of Cell Biology}, year={2002}, volume={156}, pages={13 - 16} }