title: Laminin promotes metalloproteinase-mediated dystroglycan processing to regulate oligodendrocyte progenitor cell proliferation.
abstract: The cell surface receptor dystroglycan mediates interactions between oligodendroglia and laminin-211, an extracellular matrix protein that regulates timely oligodendroglial development. However, dystroglycan's precise role in oligodendroglial development and the potential mechanisms to regulate laminin-dystroglycan interactions remain unknown. Here we report that oligodendroglial dystroglycan is cleaved by metalloproteinases, thereby uncoupling oligodendroglia from laminin binding. Dystroglycan cleavage is selectively stimulated by oligodendrocyte progenitor cell attachment to laminin-211, but not laminin-111 or poly-D-lysine. In addition, dystroglycan cleavage occurs most prominently in oligodendrocyte progenitor cells, with limited dystroglycan cleavage observed in differentiating oligodendrocytes. When dystroglycan cleavage is blocked by metalloproteinase inhibitors, oligodendrocyte progenitor cell proliferation is substantially decreased. Conversely, expression of the intracellular portion of cleaved dystroglycan results in increased oligodendrocyte progenitor cell proliferation, suggesting that endogenous dystroglycan cleavage may promote oligodendrocyte progenitor cell cycle progression. Intriguingly, while matrix metalloproteinase-2 and/or -9 have been reported to be responsible for dystroglycan cleavage, we find that these two metalloproteinases are neither necessary nor sufficient for cleavage of oligodendroglial dystroglycan. In summary, laminin-211 stimulates metalloproteinase-mediated dystroglycan cleavage in oligodendrocyte progenitor cells (but not in differentiated oligodendrocytes), which in turn promotes oligodendrocyte progenitor cell proliferation. This novel regulation of oligodendroglial laminin-dystroglycan interactions may have important consequences for oligodendroglial differentiation, both during development and during disease when metalloproteinase levels become elevated.
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Cindy V
authors.initials: CV
authors.lastname: Leiton
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Azeez
authors.initials: A
authors.lastname: Aranmolate
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Eyermann
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Menezes
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Luisa F
authors.initials: LF
authors.lastname: Escobar-Hoyos
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Solomon
authors.initials: S
authors.lastname: Husain
authors.affiliation: Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield, UK.
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Winder
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Colognato
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D049030:Dystroglycans / Q000378:metabolism*; D005260:Female; D007797:Laminin / Q000494:pharmacology*; D045726:Metalloproteases / Q000502:physiology*; D051379:Mice; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*
chemical_list: D007797:Laminin; D049030:Dystroglycans; D045726:Metalloproteases
keywords: dystroglycan; laminin; metalloproteinase; myelin; oligodendrocyte progenitor cell; proliferation