TACE (ADAM17) inhibits Schwann cell myelination

Rosa La Marca, Federica Cerri, Keisuke Horiuchi, Angela Bachi, M. Laura Feltri, Lawrence Wrabetz, Carl P. Blobel, Angelo Quattrini, James L. Salzer, Carla Taveggia

Research output: Contribution to journalArticle

Abstract

Tumor necrosis factor-"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.

Original languageEnglish
Pages (from-to)857-865
Number of pages9
JournalNature Neuroscience
Volume14
Issue number7
DOIs
Publication statusPublished - Jul 2011

ASJC Scopus subject areas

  • Neuroscience(all)

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    La Marca, R., Cerri, F., Horiuchi, K., Bachi, A., Feltri, M. L., Wrabetz, L., Blobel, C. P., Quattrini, A., Salzer, J. L., & Taveggia, C. (2011). TACE (ADAM17) inhibits Schwann cell myelination. Nature Neuroscience, 14(7), 857-865. https://doi.org/10.1038/nn.2849