title: Membrane-type matrix metalloproteinase-3 regulates neuronal responsiveness to myelin through Nogo-66 receptor 1 cleavage.
abstract: Nogo-66 receptor 1 (NgR1) is a glycosylphosphatidylinositol-anchored receptor for myelin-associated inhibitors that restricts plasticity and axonal regrowth in the CNS. NgR1 is cleaved from the cell surface of SH-SY5Y neuroblastoma cells in a metalloproteinase-dependent manner; however, the mechanism and physiological consequence of NgR1 shedding have not been explored. We now demonstrate that NgR1 is shed from multiple populations of primary neurons. Through a loss-of-function approach, we found that membrane-type matrix metalloproteinase-3 (MT3-MMP) regulates endogenous NgR1 shedding in primary neurons. Neuronal knockdown of MT3-MMP resulted in the accumulation of NgR1 at the cell surface and reduced the accumulation of the NgR1 cleavage fragment in medium conditioned by cortical neurons. Recombinant MT1-, MT2-, MT3-, and MT5-MMPs promoted NgR1 shedding from the surface of primary neurons, and this treatment rendered neurons resistant to myelin-associated inhibitors. Introduction of a cleavage-resistant form of NgR1 reconstitutes the neuronal response to these inhibitors, demonstrating that specific metalloproteinases attenuate neuronal responses to myelin in an NgR1-dependent manner.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Gino B
authors.initials: GB
authors.lastname: Ferraro
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Morrison
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Overall
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
authors.forename: Alyson E
authors.initials: AE
authors.lastname: Fournier
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D058851:GPI-Linked Proteins / Q000032:analysis / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D053513:Matrix Metalloproteinase 16 / Q000502:physiology*; D000090023:Metallothionein 3; D051379:Mice; D009185:Myelin Proteins / Q000032:analysis / Q000378:metabolism*; D009186:Myelin Sheath; D009474:Neurons / Q000166:cytology / Q000502:physiology; D000070816:Nogo Receptor 1; D010446:Peptide Fragments / Q000032:analysis; D051381:Rats; D011956:Receptors, Cell Surface / Q000032:analysis / Q000378:metabolism*
chemical_list: D058851:GPI-Linked Proteins; D000090023:Metallothionein 3; C507104:Mmp16 protein, mouse; C000715430:Mt3 protein, mouse; D009185:Myelin Proteins; D000070816:Nogo Receptor 1; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C419790:Rtn4r protein, mouse; D053513:Matrix Metalloproteinase 16