Myelination in the peripheral nervous system requires close contact between Schwann cells and the axon, but the underlying molecular basis remains largely unknown. Here we show that cell adhesion molecules (CAMs) of the nectin-like (Necl, also known as SynCAM or Cadm) family mediate Schwann cell–axon interaction during myelination. Necl4 is the main Necl expressed by myelinating Schwann cells and is located along the internodes in direct apposition to Necl1, which is localized on axons. Necl4 serves as the glial binding partner for axonal Necl1, and the interaction between these two CAMs mediates Schwann cell adhesion. The disruption of the interaction between Necl1 and Necl4 by their soluble extracellular domains, or the expression of a dominant-negative Necl4 in Schwann cells, inhibits myelination. These results suggest that Necl proteins are important for mediating axon-glia contact during myelination in peripheral nerves.
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Jessen, K.R. & Mirsky, R. The origin and development of glial cells in peripheral nerves. Nat. Rev. Neurosci. 6, 671–682 (2005).
Michailov, G.V. et al. Axonal neuregulin-1 regulates myelin sheath thickness. Science 304, 700–703 (2004).
Taveggia, C. et al. Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 47, 681–694 (2005).
Wanner, I.B. & Wood, P.M. N-cadherin mediates axon-aligned process growth and cell-cell interaction in rat Schwann cells. J. Neurosci. 22, 4066–4079 (2002).
Wanner, I.B. et al. Role of N-cadherin in Schwann cell precursors of growing nerves. Glia 54, 439–459 (2006).
Tait, S. et al. An oligodendrocyte cell adhesion molecule at the site of assembly of the paranodal axo-glial junction. J. Cell Biol. 150, 657–666 (2000).
Traka, M., Dupree, J.L., Popko, B. & Karagogeos, D. The neuronal adhesion protein TAG-1 is expressed by Schwann cells and oligodendrocytes and is localized to the juxtaparanodal region of myelinated fibers. J. Neurosci. 22, 3016–3024 (2002).
Eshed, Y. et al. Gliomedin mediates Schwann cell-axon interaction and the molecular assembly of the nodes of Ranvier. Neuron 47, 215–229 (2005).
Poliak, S. et al. Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1. J. Cell Biol. 162, 1149–1160 (2003).
Sherman, D.L. et al. Neurofascins are required to establish axonal domains for saltatory conduction. Neuron 48, 737–742 (2005).
Seilheimer, B., Persohn, E. & Schachner, M. Antibodies to the L1 adhesion molecule inhibit Schwann cell ensheathment of neurons in vitro. J. Cell Biol. 109, 3095–3103 (1989).
Owens, G.C., Boyd, C.J., Bunge, R.P. & Salzer, J.L. Expression of recombinant myelin-associated glycoprotein in primary Schwann cells promotes the initial investment of axons by myelinating Schwann cells. J. Cell Biol. 111, 1171–1182 (1990).
Haney, C.A. et al. Heterophilic binding of L1 on unmyelinated sensory axons mediates Schwann cell adhesion and is required for axonal survival. J. Cell Biol. 146, 1173–1184 (1999).
Li, C. et al. Myelination in the absence of myelin-associated glycoprotein. Nature 369, 747–750 (1994).
Montag, D. et al. Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. Neuron 13, 229–246 (1994).
Bartsch, U. Neural CAMS and their role in the development and organization of myelin sheaths. Front. Biosci. 8, d477–d490 (2003).
Poliak, S. & Peles, E. The local differentiation of myelinated axons at nodes of Ranvier. Nat. Rev. Neurosci. 4, 968–980 (2003).
Spiegel, I. & Peles, E. Cellular junctions of myelinated nerves (Review). Mol. Membr. Biol. 19, 95–101 (2002).
Spiegel, I. et al. Identification of novel cell-adhesion molecules in peripheral nerves using a signal-sequence trap. Neuron Glia Biol. 2, 27–38 (2006).
Biederer, T. Bioinformatic characterization of the SynCAM family of immunoglobulin-like domain-containing adhesion molecules. Genomics 87, 139–150 (2006).
Takai, Y. & Nakanishi, H. Nectin and afadin: novel organizers of intercellular junctions. J. Cell Sci. 116, 17–27 (2003).
Fukuhara, H. et al. Association of a lung tumor suppressor TSLC1 with MPP3, a human homologue of Drosophila tumor suppressor Dlg. Oncogene 22, 6160–6165 (2003).
Shingai, T. et al. Implications of nectin-like molecule-2/IGSF4/RA175/SgIGSF/TSLC1/SynCAM1 in cell-cell adhesion and transmembrane protein localization in epithelial cells. J. Biol. Chem. 278, 35421–35427 (2003).
Yageta, M. et al. Direct association of TSLC1 and DAL-1, two distinct tumor suppressor proteins in lung cancer. Cancer Res. 62, 5129–5133 (2002).
Zhou, Y. et al. Nectin-like molecule 1 is a protein 4.1N associated protein and recruits protein 4.1N from cytoplasm to the plasma membrane. Biochim. Biophys. Acta 1669, 142–154 (2005).
Biederer, T. et al. SynCAM, a synaptic adhesion molecule that drives synapse assembly. Science 297, 1525–1531 (2002).
Kakunaga, S. et al. Nectin-like molecule-1/TSLL1/SynCAM3: a neural tissue-specific immunoglobulin-like cell-cell adhesion molecule localizing at non-junctional contact sites of presynaptic nerve terminals, axons and glia cell processes. J. Cell Sci. 118, 1267–1277 (2005).
Williams, Y.N. et al. Cell adhesion and prostate tumor-suppressor activity of TSLL2/IGSF4C, an immunoglobulin superfamily molecule homologous to TSLC1/IGSF4. Oncogene 25, 1446–1453 (2006).
Irie, K., Shimizu, K., Sakisaka, T., Ikeda, W. & Takai, Y. Roles and modes of action of nectins in cell-cell adhesion. Semin. Cell Dev. Biol. 15, 643–656 (2004).
Sara, Y. et al. Selective capability of SynCAM and neuroligin for functional synapse assembly. J. Neurosci. 25, 260–270 (2005).
Fujita, E., Urase, K., Soyama, A., Kouroku, Y. & Momoi, T. Distribution of RA175/TSLC1/SynCAM, a member of the immunoglobulin superfamily, in the developing nervous system. Brain Res. Dev. Brain Res. 154, 199–209 (2005).
Ohta, Y. et al. Spatiotemporal patterns of expression of IGSF4 in developing mouse nervous system. Brain Res. Dev. Brain Res. 156, 23–31 (2005).
Koticha, D. et al. Neurofascin interactions play a critical role in clustering sodium channels, ankyrin G and beta IV spectrin at peripheral nodes of Ranvier. Dev. Biol. 293, 1–12 (2006).
Lustig, M. et al. Nr-CAM and neurofascin interactions regulate ankyrin G and sodium channel clustering at the node of Ranvier. Curr. Biol. 11, 1864–1869 (2001).
Koroll, M., Rathjen, F.G. & Volkmer, H. The neural cell recognition molecule neurofascin interacts with syntenin-1, but not with syntenin-2, both of which reveal self-associating activity. J. Biol. Chem. 276, 10646–10654 (2001).
Gunn-Moore, F.J. et al. A functional FERM domain binding motif in neurofascin. Mol. Cell. Neurosci. 33, 441–446 (2006).
Hall, S.M. & Gregson, N.A. The in vivo and ultrastructural effects of injection of lysophosphatidyl choline into myelinated peripheral nerve fibres of the adult mouse. J. Cell Sci. 9, 769–789 (1971).
Thomas, P.K. & Olsson, Y. Microscopic anatomy and function of the connective tissue components of peripheral nerve. in Peripheral Neuropathy (eds. Dyck, P.J., Thomas, P.K., Lambert, E.H. and Bunge, R.) 97–120 (W.B. Saunders., Philadelphia, 1984).
Dugandzija-Novakovic, S., Koszowski, A.G., Levinson, S.R. & Shrager, P. Clustering of Na+ channels and node of Ranvier formation in remyelinating axons. J. Neurosci. 15, 492–503 (1995).
Lemke, G. & Axel, R. Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin. Cell 40, 501–508 (1985).
Dong, X. et al. Crystal structure of the V domain of human Nectin-like molecule-1/Syncam3/Tsll1/Igsf4b, a neural tissue–specific immunoglobulin-like cell-cell adhesion molecule. J. Biol. Chem. 281, 10610–10617 (2006).
Ohno, N. et al. Expression of protein 4.1G in Schwann cells of the peripheral nervous system. J. Neurosci. Res. 84, 568–577 (2006).
Poliak, S., Matlis, S., Ullmer, C., Scherer, S.S. & Peles, E. Distinct claudins and associated PDZ proteins form different autotypic tight junctions in myelinating Schwann cells. J. Cell Biol. 159, 361–372 (2002).
Trapp, B.D., Andrews, S.B., Wong, A., O'Connell, M. & Griffin, J.W. Colocalization of the myelin-associated glycoprotein and the microfilament components, F-actin and spectrin, in Schwann cells of myelinated nerve fibres. J. Neurocytol. 18, 47–60 (1989).
Chan, J.R. et al. The polarity protein Par-3 directly interacts with p75NTR to regulate myelination. Science 314, 832–836 (2006).
Spiegel, I., Salomon, D., Erne, B., Schaeren-Wiemers, N. & Peles, E. Caspr3 and caspr4, two novel members of the caspr family, are expressed in the nervous system and interact with PDZ domains. Mol. Cell. Neurosci. 20, 283–297 (2002).
Sokal, R.R. & Rohlf, F.J. Biometry: The Principles and Practice of Statistics in Biological Research (W.H. Freeman & Company, New York, 1994).
Schafer, D.P., Bansal, R., Hedstrom, K.L., Pfeiffer, S.E. & Rasband, M.N. Does paranode formation and maintenance require partitioning of neurofascin 155 into lipid rafts? J. Neurosci. 24, 3176–3185 (2004).
We would like to thank Y. Takai for his generous gift of plasmids and antibodies and J. Chan for his comments. This work was supported by US National Institutes of Health grants NS50220 (E.P.) and NS044916 (M.N.R.), the National Multiple Sclerosis Society, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation's Adelson Program in Neural Repair and Rehabilitation, the US-Israel Binational Science Foundation and the Wolgin Prize for Scientific Excellence (E.P.).
The authors declare no competing financial interests.
Specificity of the antibodies to Necl4. (PDF 519 kb)
Specific immunolabeling for Necl1 and Necl4 in sciatic nerve. (PDF 491 kb)
Necl4 is absent from non–myelinating Schwann cells. (PDF 2734 kb)
Homophilic and heterophilic binding of Necls. (PDF 656 kb)
Necl4–Fc, but not MAG–Fc inhibits myelination. (PDF 1424 kb)
Expression of GFP–Necl4CT and GFP–NF155CT. (PDF 335 kb)
Summary of the different names used for the CADM gene family. (PDF 87 kb)
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Spiegel, I., Adamsky, K., Eshed, Y. et al. A central role for Necl4 (SynCAM4) in Schwann cell–axon interaction and myelination. Nat Neurosci 10, 861–869 (2007). https://doi.org/10.1038/nn1915
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