Olig2 regulates Sox10 expression in oligodendrocyte precursors through an evolutionary conserved distal enhancer.
Olig2 regulates Sox10 expression in oligodendrocyte precursors through an evolutionary conserved distal enhancer.
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DOI：
10.1093/nar/gkq951
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发表时间：
2011-03
影响因子：
14.9
通讯作者：
Wegner M
中科院分区：
文献类型：
--
作者：
Küspert M;Hammer A;Bösl MR;Wegner M
HMG结构域转录因子Sox 10在整个少突胶质细胞发育过程中表达，是这些髓鞘形成的CNS神经胶质细胞中转录调控网络的重要组成部分。在已知的Sox 10调控区中，只有位于Sox 10基因远端5′侧翼的进化保守的U2增强子表现出少突胶质细胞活性。我们发现U2在少突胶质细胞前体中有活性，但在成熟的少突胶质细胞中没有。U2活性也没有介导指定后的初始Sox 10诱导，认为少突胶质细胞发育期间Sox 10的表达取决于多个调节区的活性。少突胶质细胞bHLH转录因子Olig 2，但不是密切相关的Olig 1有效地激活U2增强子。Olig 2直接在几个位点结合U2，包括U2核心中高度保守的位点。该位点的失活废除了U2在体内的少突胶质细胞活性。与Olig 2相反，同源结构域转录因子Nkx6.2抑制U2活性。抑制可能涉及Nkx6.2向U2的募集以及Olig 2和其他激活剂通过蛋白质-蛋白质相互作用的失活。考虑到Nkx6.2在特化时和分化的少突胶质细胞中的选择性表达，Nkx6.2可能参与将U2活性限制在少突胶质细胞发育期间的前体阶段。
The HMG-domain transcription factor Sox10 is expressed throughout oligodendrocyte development and is an important component of the transcriptional regulatory network in these myelin-forming CNS glia. Of the known Sox10 regulatory regions, only the evolutionary conserved U2 enhancer in the distal 5′-flank of the Sox10 gene exhibits oligodendroglial activity. We found that U2 was active in oligodendrocyte precursors, but not in mature oligodendrocytes. U2 activity also did not mediate the initial Sox10 induction after specification arguing that Sox10 expression during oligodendroglial development depends on the activity of multiple regulatory regions. The oligodendroglial bHLH transcription factor Olig2, but not the closely related Olig1 efficiently activated the U2 enhancer. Olig2 bound U2 directly at several sites including a highly conserved one in the U2 core. Inactivation of this site abolished the oligodendroglial activity of U2 in vivo. In contrast to Olig2, the homeodomain transcription factor Nkx6.2 repressed U2 activity. Repression may involve recruitment of Nkx6.2 to U2 and inactivation of Olig2 and other activators by protein–protein interactions. Considering the selective expression of Nkx6.2 at the time of specification and in differentiated oligodendrocytes, Nkx6.2 may be involved in limiting U2 activity to the precursor stage during oligodendrocyte development.
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