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Laminin promotes metalloproteinase‐mediated dystroglycan processing to regulate oligodendrocyte progenitor cell proliferation
Author(s) -
Leiton Cindy V.,
Aranmolate Azeez,
Eyermann Christopher,
Menezes Michael J.,
EscobarHoyos Luisa F.,
Husain Solomon,
Winder Steve J.,
Colognato Holly
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13241
Subject(s) - dystroglycan , laminin , microbiology and biotechnology , metalloproteinase , oligodendrocyte , progenitor cell , progenitor , neuroscience , biology , chemistry , matrix metalloproteinase , stem cell , myelin , biochemistry , central nervous system , extracellular matrix
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.A subset of dystroglycan expressed in oligodendrocyte progenitors is cleaved by (1) a metalloproteinase, and, predicted, (2) by a γ‐secretase to generate an intracellular β−dystroglycan fragment. Cleavage occurs preferentially following attachment to the dystroglycan extracellular ligand, laminin‐211. The intracellular portion of cleaved dystroglycan then promotes oligodendrocyte progenitor proliferation, providing a novel reciprocal mechanism by which laminin–dystroglycan interactions influence oligodendroglial development. MMP, matrix metalloproteinase.