A central role for Necl4 (SynCAM4) in Schwann cell–axon interaction and myelination

Abstract

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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Figure 1: Differential expression of Necl proteins in the PNS.
Figure 2: Axonal contact and myelination are associated with increased expression of Necl4 in Schwann cells.
Figure 3: Necl4 and Necl1 are localized along the internodes.
Figure 4: Necl4 is the glial binding partner for axonal Necl1.
Figure 5: Interaction between Necl4 and Necl1 mediates Ca2+-independent adhesion of Schwann cells.
Figure 6: Necl-mediated axon-glia interaction is required for myelination.
Figure 7: Expression of a dominant-negative Necl4 inhibits myelination.
Figure 8: Necl4-Fc inhibits remyelination in vivo.

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Acknowledgements

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.).

Author information

I.S. cloned and constructed all expression constructs and probes, generated and purified antibodies, and designed and performed most of the experiments. He was assisted by R.M. in analyzing the myelination data. K.A. performed the cell adhesion assay. O.S.N. and S.S.S contributed to gene expression analysis, Y.E. to the coculture experiments and I.H. to the immunohistochemical analysis. H.S. performed the electron microscopy and M.N.R. conducted the remyelination experiments. E.P. headed the project and prepared the manuscript.

Correspondence to Elior Peles.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Specificity of the antibodies to Necl4. (PDF 519 kb)

Supplementary Fig. 2

Specific immunolabeling for Necl1 and Necl4 in sciatic nerve. (PDF 491 kb)

Supplementary Fig. 3

Necl4 is absent from non–myelinating Schwann cells. (PDF 2734 kb)

Supplementary Fig. 4

Homophilic and heterophilic binding of Necls. (PDF 656 kb)

Supplementary Fig. 5

Necl4–Fc, but not MAG–Fc inhibits myelination. (PDF 1424 kb)

Supplementary Fig. 6

Expression of GFP–Necl4CT and GFP–NF155CT. (PDF 335 kb)

Supplementary Table 1

Summary of the different names used for the CADM gene family. (PDF 87 kb)

Supplementary Methods (PDF 157 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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