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 laminindystroglycan 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.

Laminins and their receptors in the CNS

“…Integrin‐β1 (Benninger et al ., ) and ‐αv (Milner & Ffrench‐Constant, ; Milner et al ., ) as well as dystroglycan (Colognato et al ., ; Leiton et al ., ) have been identified in oligodendrocytes.…”

“…It should be noted that this CNS phenotype may be due to a direct effect of laminin‐α5 in neural tube closure or caused indirectly by peripheral defects that result in death when neural tube closure occurs. In addition, loss of laminin‐α2 results in myelination defects (Relucio et al ., , , Leiton et al ., ), BBB disruption (Menezes et al ., ), as well as apical process detachment and abnormal neocortex lamination (Loulier et al ., ), in addition to a well‐characterized muscular dystrophy phenotype (Miyagoe et al ., ; Kuang et al ., ), highlighting a critical role of laminin‐α2 in brain development. Loss‐of‐function mutations on other laminin chains (α3, β2, β3, γ2, and γ3) cause phenotypes outside the CNS, and thus are not discussed here.…”

The extracellular matrix: Focus on oligodendrocyte biology and targeting CSPGs for remyelination therapies

“…Laminins are high molecular weight fibrous glycoproteins abundantly present in the endothelial basement membrane of the blood-brain barrier (Engel & Furthmayr, 1987). Laminins' myriad functions are exerted through interactions with collagen IV, HSPGs, nidogen, dystroglycan, and laminin receptors of the integrin family (Leiton et al, 2015;Novak & Kaye, 2000). Their largely structural role is mediated in part by associating with collagen IV networks through nidogen-1 (Takagi, Yang, Liu, Wang, & Springer, 2003) and perlecan (Iozzo, 2005).…”

“…knockout of the laminin-2 a2 subunit show laminin promotes OPC survival in the subventricular zone at birth, and loss of the laminin a2 gene results in delayed oligodendrocyte maturation and dysmyelination at postnatal day 21(Relucio, Menezes, Miyagoe-Suzuki, Takeda, & Colognato, 2012). Blocking dystroglycan cleavage resulted in significantly decreased OPC proliferation(Leiton et al, 2015). Blocking dystroglycan cleavage resulted in significantly decreased OPC proliferation(Leiton et al, 2015).…”

Extracellular cues influencing oligodendrocyte differentiation and (re)myelination

“…In vivo , however, it appears that there are redundant signaling pathways that control OLG survival, as loss of the laminin-2-α6β1 integrin survival pathway in Itgβ1 knockout mice can apparently be well-compensated for during development (Benninger et al, 2006; Colognato et al, 2002). In addition to the regulation of OPC survival, laminin-2 has recently been reported to regulate OPC proliferation via the stimulation of metalloproteinase-mediated dystroglycan cleavage (Leiton et al, 2015). …”