TACE (ADAM17) inhibits Schwann cell myelination
- 12 June 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Neuroscience
- Vol. 14 (7), 857-865
- https://doi.org/10.1038/nn.2849
Abstract
The authors report that TACE, the tumor necrosis factor-α–converting enzyme, regulates PNS myelination by affecting neuregulin-1 type III activity. Mice lacking TACE in motor neurons show hypermyelination. 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.This publication has 80 references indexed in Scilit:
- Metalloprotease ADAM10 Is Required for Notch1 Site 2 CleavagePublished by Elsevier BV ,2009
- Active-site determinants of substrate recognition by the metalloproteinases TACE and ADAM10Biochemical Journal, 2009
- Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticityNature Neuroscience, 2009
- Amyloid Precursor Protein Trafficking, Processing, and FunctionPublished by Elsevier BV ,2008
- Genetic deletion of BACE1 in mice affects remyelination of sciatic nervesThe FASEB Journal, 2008
- Nectin-like proteins mediate axon–Schwann cell interactions along the internode and are essential for myelinationThe Journal of cell biology, 2007
- Patterning of Muscle Acetylcholine Receptor Gene Expression in the Absence of Motor InnervationNeuron, 2001
- An Essential Role for Ectodomain Shedding in Mammalian DevelopmentScience, 1998
- Acre-transgenic mouse strain for the ubiquitous deletion ofloxP-flanked gene segments including deletion in germ cellsNucleic Acids Research, 1995
- Limb alterations in brachypodism mice due to mutations in a new member of the TGFβ-superfamilyNature, 1994