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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / deficiency
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ADAM Proteins / genetics
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ADAM Proteins / pharmacology*
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ADAM17 Protein
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Age Factors
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Amyloid Precursor Protein Secretases / metabolism
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Animals
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Animals, Newborn
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Antioxidants / pharmacology
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Ascorbic Acid / pharmacology
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Aspartic Acid Endopeptidases / metabolism
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Axons / metabolism
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Axons / pathology
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Axons / ultrastructure
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Cells, Cultured
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Coculture Techniques / methods
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Disease Models, Animal
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Embryo, Mammalian
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Femoral Nerve / metabolism
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Femoral Nerve / pathology
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Femoral Nerve / ultrastructure
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Ganglia, Spinal / cytology
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / genetics
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Gene Expression Regulation, Developmental / physiology*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Mice
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Mice, Knockout
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Microscopy, Electron, Transmission
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Motor Neurons / drug effects
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Motor Neurons / physiology
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Myelin Basic Protein / metabolism
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Myelin Sheath / drug effects*
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Myelin Sheath / metabolism
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Myelin Sheath / ultrastructure
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Neuregulin-1 / metabolism
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Neurofilament Proteins / metabolism
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Polyradiculoneuropathy / genetics
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Polyradiculoneuropathy / metabolism
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Polyradiculoneuropathy / pathology
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RNA, Small Interfering / pharmacology
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Rats
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Schwann Cells / drug effects*
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Schwann Cells / physiology
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Schwann Cells / ultrastructure
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Signal Transduction / genetics
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / methods
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transfection / methods
Substances
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Antioxidants
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Homeodomain Proteins
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Myelin Basic Protein
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Neuregulin-1
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Neurofilament Proteins
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RNA, Small Interfering
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Transcription Factors
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Hb9 protein, mouse
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse
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ADAM Proteins
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ADAM17 Protein
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ADAM17 protein, human
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Adam17 protein, mouse
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Adam17 protein, rat
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Ascorbic Acid