Tumor necrosis factor-α–converting enzyme (TACE; also known as ADAM17) is a proteolytic sheddase that is responsible for the cleavage of several membrane-bound molecules. We report that TACE cleaves neuregulin-1 (NRG1) type III in the epidermal growth factor domain, probably inactivating it (as assessed by deficient activation of the phosphatidylinositol-3-OH kinase pathway), and thereby negatively regulating peripheral nervous system (PNS) myelination. Lentivirus-mediated knockdown of TACE in vitro in dorsal root ganglia neurons accelerates the onset of myelination and results in hypermyelination. In agreement, motor neurons of conditional knockout mice lacking TACE specifically in these cells are significantly hypermyelinated, and small-caliber fibers are aberrantly myelinated. Further, reduced TACE activity rescues hypomyelination in NRG1 type III haploinsufficient mice in vivo. We also show that the inhibitory effect of TACE is neuron-autonomous, as Schwann cells lacking TACE elaborate myelin of normal thickness. Thus, TACE is a modulator of NRG1 type III activity and is a negative regulator of myelination in the PNS.
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We thank S. Arber (University of Basel) for providing the HB9-cre transgenic line, M. Filbin (Hunter College) for antibodies, P. Podini for assistance with electron microscopy, G. Dina and A. Cattaneo for technical support and Y. Poitelon for artwork. This study was supported by the Federazione Italiana Sclerosi Multipla (FISM) (grant 2007/PC/01) and the Compagnia di San Paolo (C.T.); by the US National Institute of Health (grants R01-NS045630 (M.L.F.), R01-NS055256 (L.W.), R01-GM64750 (C.P.B.) and RO1-NS26001 (J.L.S.)); by Telethon Italia (grants GGP08021 (M.L.F.), GGP071100 (L.W.) and GPP10007 (C.T., L.W. and M.L.F.)). C.T. is a recipient of a FISM Transition Career Award.
The authors declare no competing financial interests.
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La Marca, R., Cerri, F., Horiuchi, K. et al. TACE (ADAM17) inhibits Schwann cell myelination. Nat Neurosci 14, 857–865 (2011). https://doi.org/10.1038/nn.2849
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