ADAM17/TACE inhibits Schwann cell myelination

Rosa La Marca (1) , Federica Cerri (1) , Keisuke Horiuchi (1) , Angela Bachi (1) , Maria Laura Feltri (1) , Lawrence Wrabetz (1) , Carl P. Blobel (1) , Angelo Quattrini (1) , James L. Salzer (1) , Carla Taveggia (1)

1 Neuropathology Unit

TACE, the tumor necrosis factor alpha-converting enzyme, is a proteolytic sheddase responsible for the cleavage of several membrane-bound molecules. We report that TACE cleaves NRG1 type III in the EGF domain, likely inactivating it, as assessed by deficient activation of PI-3 kinase pathway, thereby negatively regulating PNS myelination. Lentiviral mediated knockdown of TACE in vitro in dorsal root ganglia neurons accelerates the onset of myelination and results in hypermyelination. In agreement, conditional knockout mice lacking TACE in motor neurons are significantly hypermyelinated and small caliber fibers aberrantly myelinated. Further, reduced TACE activity rescues NRG1 type III hypomyelination in vivo. We also show that the inhibitory effect of TACE is neuron autonomous as Schwann cells lacking TACE elaborate myelin of normal myelin thickness. Thus, TACE is a novel modulator of Neuregulin 1 type III activity and is a significantly negative regulator of myelination in the PNS.

Mots clés: Glia; Signal Transduction; Development; Differentiation; proteases; myelin

Rosa La Marca, Federica Cerri, Keisuke Horiuchi, Angela Bachi, Maria Laura Feltri, et al.. ADAM17/TACE inhibits Schwann cell myelination. Nature Neuroscience, 2011, ⟨10.1038/nn.2849⟩. ⟨hal-00650655⟩