Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651, USA.
J Neurosci Res. 2010 Nov 15;88(15):3295-307. doi: 10.1002/jnr.22484.
The adhesion receptor dystroglycan positively regulates terminal differentiation of oligodendrocytes, but the mechanism by which this occurs remains unclear. Using primary oligodendrocyte cultures, we identified and examined a connection between dystroglycan and the ability of insulin-like growth factor-1 (IGF-1) to promote oligodendrocyte differentiation. Consistent with previous reports, treatment with exogenous IGF-1 caused an increase in MBP protein that was preceded by activation of PI3K (AKT) and MAPK (ERK) signaling pathways. The extracellular matrix protein laminin was further shown to potentiate the effect of IGF-1 on oligodendrocyte differentiation. Depletion of the laminin receptor dystroglycan using siRNA, however, blocked the ability of IGF-1 to promote oligodendrocyte differentiation of cells grown on laminin, suggesting a role for dystroglycan in IGF-1-mediated differentiation. Indeed, loss of dystroglycan led to a reduction in the ability of IGF-1 to activate MAPK, but not PI3K, signaling pathways. Pharmacological inhibition of MAPK signaling also prevented IGF-1-induced increases in myelin basic protein (MBP), indicating that MAPK signaling was necessary to drive IGF-1-mediated enhancement of oligodendrocyte differentiation. Using immunoprecipitation, we found that dystroglycan, the adaptor protein Grb2, and insulin receptor substrate-1 (IRS-1), were associated in a protein complex. Taken together, our results suggest that the positive regulatory effect of laminin on oligodendrocyte differentiation may be attributed, at least in part, to dystroglycan's ability to promote IGF-1-induced differentiation.
黏附受体 dystroglycan 正向调控少突胶质细胞的终末分化，但这一过程的机制尚不清楚。我们利用原代少突胶质细胞培养物，确定并研究了 dystroglycan 与胰岛素样生长因子-1（IGF-1）促进少突胶质细胞分化的能力之间的联系。与之前的报道一致，外源性 IGF-1 的处理导致 MBP 蛋白增加，这是 PI3K（AKT）和 MAPK（ERK）信号通路激活的结果。进一步表明细胞外基质蛋白层粘连蛋白增强了 IGF-1 对少突胶质细胞分化的作用。然而，使用 siRNA 耗尽层粘连蛋白的 laminin 受体 dystroglycan，阻断了 IGF-1 促进在层粘连蛋白上生长的细胞分化为少突胶质细胞的能力，表明 dystroglycan 在 IGF-1 介导的分化中起作用。事实上，dystroglycan 的缺失导致 IGF-1 激活 MAPK 而不是 PI3K 信号通路的能力降低。MAPK 信号通路的药理学抑制也阻止了 IGF-1 诱导的髓鞘碱性蛋白（MBP）增加，表明 MAPK 信号通路是驱动 IGF-1 介导的增强少突胶质细胞分化所必需的。通过免疫沉淀，我们发现 dystroglycan、衔接蛋白 Grb2 和胰岛素受体底物-1（IRS-1）在一个蛋白复合物中相关。总之，我们的结果表明，层粘连蛋白对少突胶质细胞分化的正向调节作用可能至少部分归因于 dystroglycan 促进 IGF-1 诱导的分化的能力。
