Colognato Holly, Baron Wia, Avellana-Adalid Virginia, Relvas Jõao B, Baron-Van Evercooren Anne, Georges-Labouesse Elisabeth, ffrench-Constant Charles
Department of Medical Genetics and Center for Brain Repair, University of Cambridge, Cambridge CB2 2PY, UK.
Nat Cell Biol. 2002 Nov;4(11):833-41. doi: 10.1038/ncb865.
Depending on the stage of development, a growth factor can mediate cell proliferation, survival or differentiation. The interaction of cell-surface integrins with extracellular matrix ligands can regulate growth factor responses and thus may influence the effect mediated by the growth factor. Here we show, by using mice lacking the alpha(6) integrin receptor for laminins, that myelin-forming oligodendrocytes activate an integrin-regulated switch in survival signalling when they contact axonal laminins. This switch alters survival signalling mediated by neuregulin from dependence on the phosphatidylinositol-3-OH kinase (PI(3)K) pathway to dependence on the mitogen-activated kinase pathway. The consequent enhanced survival provides a mechanism for target-dependent selection during development of the central nervous system. This integrin-regulated switch reverses the capacity of neuregulin to inhibit the differentiation of precursors, thereby explaining how neuregulin subsequently promotes differentiation and survival in myelinating oligodendrocytes. Our results provide a general mechanism by which growth factors can exert apparently contradictory effects at different stages of development in individual cell lineages.
根据发育阶段的不同，生长因子可介导细胞增殖、存活或分化。细胞表面整合素与细胞外基质配体的相互作用可调节生长因子反应，进而可能影响生长因子介导的效应。在此，我们通过使用缺乏层粘连蛋白α(6)整合素受体的小鼠表明，形成髓鞘的少突胶质细胞在接触轴突层粘连蛋白时会激活一种整合素调节的存活信号开关。这种开关改变了由神经调节蛋白介导的存活信号，从依赖磷脂酰肌醇-3-OH激酶（PI(3)K）途径转变为依赖丝裂原活化激酶途径。由此增强的存活为中枢神经系统发育过程中的靶标依赖性选择提供了一种机制。这种整合素调节的开关逆转了神经调节蛋白抑制前体细胞分化的能力，从而解释了神经调节蛋白随后如何促进有髓鞘少突胶质细胞的分化和存活。我们的结果提供了一种普遍机制，通过该机制生长因子可在单个细胞谱系发育的不同阶段发挥明显矛盾的作用。
