Evidence that nucleocytoplasmic Olig2 translocation mediates brain-injury-induced differentiation of glial precursors to astrocytes
Evidence that nucleocytoplasmic Olig2 translocation mediates brain-injury-induced differentiation of glial precursors to astrocytes
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DOI：
10.1002/jnr.21368
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发表时间：
2007-08-01
影响因子：
4.2
通讯作者：
Mattson, Mark P.
中科院分区：
文献类型：
--
作者：
Magnus, Tim;Coksaygan, Turhan;Mattson, Mark P.
成人大脑中的神经和神经胶质祖细胞对组织损伤做出反应的机制尚不清楚。我们在大鼠和两种转基因小鼠模型中研究了这些细胞对刺伤的反应，其中 Y/GFP 由 Sox2（神经干细胞标记物）或 T alpha-1（标记新生神经元）驱动。所有非神经发生区域的神经祖细胞的反应都很低，并且损伤部位没有发生神经发生。表达 Olig2 和 NG2 的神经胶质祖细胞表现出最大的反应。这些祖细胞的出现先于反应性星形胶质细胞的出现。令人惊讶的是，我们发现了转录因子 Olig2 在损伤后第一周易位到细胞质中的证据，这是已知在大脑发育过程中介导星形胶质细胞分化的机制。将神经胶质祖细胞暴露于血清成分或通过上调 Notch-1 的骨形态发生蛋白后，在体外重现了 Olig2 的易位、NG2 的下调以及神经胶质原纤维酸性蛋白表达的增加。 γ-分泌酶抑制剂 DAPT 抑制 Notch-1 可以阻断神经胶质分化和 Olig2 易位。总之，这些数据表明，大量 Olig2(+) 神经胶质祖细胞迅速成熟为星形胶质细胞是创伤后修复过程的基础。相比之下，神经干细胞和神经元祖细胞似乎在受损的成体中枢神经系统中只发挥次要作用。 (c) 2007 年 Wiley-Liss, Inc.
The mechanisms by which neural and glial progenitor cells in the adult brain respond to tissue injury are unknown. We studied the responses of these cells to stab wound injury in rats and in two transgenic mouse models in which Y/GFP is driven either by Sox2 (a neural stem cell marker) or by T alpha-1 (which marks newly born neurons). The response of neural progenitors was low in all nonneurogenic regions, and no neurogenesis occurred at the injury site. Glial progenitors expressing Olig2 and NG2 showed the greatest response. The appearance of these progenitors preceded the appearance of reactive astrocytes. Surprisingly, we found evidence of the translocation of the transcription factor Olig2 into cytoplasm in the first week after injury, a mechanism that is known to mediate the differentiation of astrocytes during brain development. Translocation of Olig2, down-regulation of NG2, and increased glial fibrillary acidic protein expression were recapitulated in vitro after exposure of glial progenitors to serum components or bone morphogentic protein by up-regulation of Notch-1. The glial differentiation and Olig2 translocation could be blocked by inhibition of Notch-1 with the gamma-secretase inhibitor DAPT. Together, these data indicate that the prompt maturation of numerous Olig2(+) glial progenitors to astrocytes underlies the repair process after a traumatic injury. In contrast, neural stem cells and neuronal progenitor cells appear to play only a minor role in the injured adult CNS. (c) 2007 Wiley-Liss, Inc.