title: 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.
authors.affiliation: Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: La Marca
authors.forename: Federica
authors.initials: F
authors.lastname: Cerri
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horiuchi
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.forename: M Laura
authors.initials: ML
authors.lastname: Feltri
authors.forename: Lawrence
authors.initials: L
authors.lastname: Wrabetz
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.forename: James L
authors.initials: JL
authors.lastname: Salzer
authors.forename: Carla
authors.initials: C
authors.lastname: Taveggia
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D000072198:ADAM17 Protein; D000367:Age Factors; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001369:Axons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005267:Femoral Nerve / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005727:Ganglia, Spinal / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D020890:Neuregulin-1 / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D011129:Polyradiculoneuropathy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D012583:Schwann Cells / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D015398:Signal Transduction / Q000235:genetics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D000975:Antioxidants; D018398:Homeodomain Proteins; D004676:Myelin Basic Protein; D020890:Neuregulin-1; D016900:Neurofilament Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C084059:Hb9 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat; D001205:Ascorbic Acid