Laminin alters fyn regulatory mechanisms and promotes oligodendrocyte development.
Laminin alters fyn regulatory mechanisms and promotes oligodendrocyte development.
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DOI：
10.1523/jneurosci.0888-09.2009
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发表时间：
2009-09-23
期刊：
影响因子：
--
通讯作者：
Colognato H
中科院分区：
文献类型：
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作者：
Relucio J;Tzvetanova ID;Ao W;Lindquist S;Colognato H
LAMA2（细胞外基质蛋白层粘连蛋白-α2的基因）的突变会导致严重的肌营养不良，称为MDC1A。MDC1A患者伴有中枢神经发育不良和白质异常，其潜在机制尚不清楚。在这里，我们报告了在层粘连蛋白缺乏的小鼠中，少突胶质细胞的发育被延迟，以至于少突胶质细胞祖细胞在成年大脑中不适当地积累。相反，层粘连蛋白底物被发现促进少突胶质细胞祖细胞向新形成的少突胶质细胞的转变。层粘连蛋白增强的分化依赖于Src家族激酶，并导致Src家族激酶Fyn的激活。然而，在层粘连蛋白缺乏的大脑中，Fyn抑制的增加伴随着Src家族激酶负调控蛋白c端Src激酶（Csk）及其跨膜接头Csk结合蛋白（Cbp）水平的升高。这些发现表明，层粘连蛋白缺乏通过引起对少突胶质细胞发育至关重要的信号通路失调而延迟少突胶质细胞成熟，并表明CNS层粘连蛋白的正常作用是通过调节Fyn调节分子促进少突胶质细胞祖细胞向髓磷脂形成的少突胶质细胞的发育。
Mutations in LAMA2, the gene for the extracellular matrix protein laminin-α2, cause a severe muscular dystrophy termed MDC1A. MDC1A patients have accompanying CNS neural dysplasias and white matter abnormalities for which the underlying mechanisms remain unknown. Here we report that in laminin-deficient mice oligodendrocyte development was delayed such that oligodendrocyte progenitors accumulated inappropriately in adult brains. Conversely, laminin substrates were found to promote the transition of oligodendrocyte progenitors to newly-formed oligodendrocytes. Laminin-enhanced differentiation was Src Family Kinase –dependent and resulted in the activation of the Src Family Kinase Fyn. In laminin-deficient brains, however, increased Fyn repression was accompanied by elevated levels of the Src Family Kinase negative regulatory proteins, C-terminal Src kinase (Csk) and its transmembrane adaptor, Csk-binding protein (Cbp). These findings indicate that laminin deficiencies delay oligodendrocyte maturation by causing dysregulation of signaling pathways critical for oligodendrocyte development, and suggest that a normal role for CNS laminin is to promote the development of oligodendrocyte progenitors into myelin-forming oligodendrocytes via modulation of Fyn regulatory molecules.