TACE (ADAM17) inhibits Schwann cell myelination

Abstract

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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Figure 1: TACE downregulation induces precocious myelination and hypermyelination in vitro.
Figure 2: In vitro hypermyelination is neuron-autonomous.
Figure 3: TACE inactivation in motor neurons leads to precocious myelination.
Figure 4: HB9-cre; Tacefl/fl mice are hypermyelinated during development.
Figure 5: HB9-cre; Tacefl/fl adult mice were hypermyelinated and Remak fibers were aberrantly ensheathed.
Figure 6: Mpz-cre; Tacefl/fl mice were normally myelinated.
Figure 7: TACE cleaves NRG1 type III.
Figure 8: TACE regulates NRG1 type III activity.

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Acknowledgements

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.

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R.L.M. conducted most of the experiments. F.C. and A.Q. performed morphological and ultrastructural analyses of sciatic nerves and ventral roots. K.H., C.P.B., M.L.F. and L.W. provided transgenic lines and helped with discussions. A.B. performed the mass spectrometry analyses. J.L.S. provided support and initially contributed to the experimental design. C.T. designed the experimental plan, supervised the project and wrote the paper. All authors commented on the paper.

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Correspondence to Carla Taveggia.

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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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