| The extracellular matrix (ECM) protein, laminin-2 regulates the ability of oligodendrocytes to orchestrate myelin synthesis in the central nervous system (CNS). However, the mechanism by which this occurs remains unclear. While integrin receptors are known to transmit laminin signals in oligodendrocytes, their role in laminin-mediated myelinogenesis appears to be limited as oligodendrocytes with deleted or disrupted beta1 integrin exhibit only marginal myelin defects compared to those observed in laminin-deficient animals. Here, we report that oligodendrocytes also express the non-integrin laminin receptor, dystroglycan, and reveal it as a novel regulator of myelin formation. Using primary oligodendrocytes, we find that dystroglycan expression correlated with and was necessary for optimum differentiation. That is, higher levels of dystroglycan were found in cells expressing myelin specific proteins while the ablation of dystroglycan resulted in a significant reduction in myelin specific proteins. Subsequent to these findings, we revealed a novel functional connection between dystroglycan and insulin-like growth factor-1 (IGF-1) signaling. As described previously, treatment with exogenous IGF-1 caused an increase in myelin-specific proteins that was preceded by activation of PI3K (AKT) and MAPK (ERK) signaling pathways. Moreover, laminin-2 was shown to potentiate the effect of IGF-1 on oligodendrocyte differentiation, whereas dystroglycan depletion reversed it. In addition, depletion of dystroglycan led to a reduction in the ability of IGF-1 to activate MAPK, but not PI3K signaling pathways. Consistent with these observations, pharmacological inhibition of MAPK signaling prevented IGF-1-induced increases in myelin-specific proteins in the presence of laminin, indicating that MAPK signaling was necessary to drive IGF-1-mediated enhancement of oligodendrocyte differentiation. Finally, we found that dystroglycan, the adapter protein GRB2, and insulin receptor substrate-1 (IRS1), were associated in a protein complex. Taken together, we've identified the non-integrin receptor dystroglycan as a novel mediator of laminin-2-induced myelinogenesis in oligodendrocytes. We've also provided evidence that the effects of dystroglycan are attributed, at least in part to its ability to promote IGF-1-induced activation of MAPK/ERK signaling, possibly through a structural association with IRS1 and GRB2. |
