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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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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