Regulation of axonal calibers by myelinating Schwann cells in the peripheral nervous system

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Rapid, saltatory nerve conduction in the peripheral nervous system is facilitated by the myelination of axons by Schwann cells. We hypothesize that the close developmental, morphological and functional association of myelinated axons with their myelinating Schwann cells involves relevant, but yet unknown proteins at the axon/myelin-interface. In a pilot experiment we biochemically enriched the axon/myelin-interface of mouse sciatic nerves and subjected this fraction to proteome analysis. To select proteins for more detailed characterization, we evaluated our dataset for proteins that are probably involved in cell-to-cell signaling. We identified CMTM6 (chemokine-like factor-like MARVEL-transmembrane domain-containing protein 6) as a novel constituent of the adaxonal plasma membrane of myelinating Schwann cells and genetically disrupted its expression. Based on our unpublished observations we propose to pursue the concept that CMTM6 restricts the radial growth of myelinated axons in the PNS while it is not required for myelin biogenesis per se. This project will involve biochemistry/proteomics, mouse genetics, electron microscopy, and assessment of nerve conduction velocity and mouse behavior. Cmtm6-mutant mice provide a unique model to test the hypothesis that myelinating Schwann cells restrict the calibers of myelinated axons via adaxonal surface molecules including CMTM6; this novel concept will be tested in vivo.