Ascl1/Mash1 promotes brain oligodendrogenesis during myelination and remyelination.
Ascl1/Mash1 promotes brain oligodendrogenesis during myelination and remyelination.
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DOI：
10.1523/jneurosci.0805-13.2013
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发表时间：
2013-06-05
期刊：
影响因子：
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通讯作者：
Parras C
中科院分区：
文献类型：
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作者：
Nakatani H;Martin E;Hassani H;Clavairoly A;Maire CL;Viadieu A;Kerninon C;Delmasure A;Frah M;Weber M;Nakafuku M;Zalc B;Thomas JL;Guillemot F;Nait-Oumesmar B;Parras C
少突胶质细胞是中枢神经系统的髓鞘形成细胞。它们从少突胶质细胞前体细胞（OPC）分化，少突胶质细胞前体细胞（OPC）在整个生命过程中由祖细胞产生，但在新生期和对脱髓鞘损伤的反应中更活跃。在这些发育或修复过程中需要精确调节少突胶质细胞的发生。我们假设这种调节涉及转录因子，这些转录因子由OPCs和/或其祖细胞表达。Ascl 1/Mash 1是一种前神经转录因子，以前与胚胎少突胶质细胞发生有关，并与寡聚体2（少突胶质细胞发育中的一种重要转录调节因子）进行遗传相互作用。在此，我们研究了Ascl 1对出生后皮质中少突胶质细胞发育和髓鞘再生的贡献。在新生儿期，Ascl 1的表达检测皮质室管膜下区和皮质OPCs的祖细胞。不同的遗传方法删除Ascl 1在皮质祖细胞或OPC减少新生儿少突分化，表明Ascl 1积极调节两个OPC规范室管膜下区祖细胞以及OPC分化和增殖之间的平衡。在小鼠胼胝体局灶性脱髓鞘模型和人类多发性硬化病变中对髓鞘再生过程的检查表明，Ascl 1活性沿着在髓鞘再生病变中观察到的少突胶质细胞生成增加而上调。其他遗传证据表明，髓鞘再生少突胶质细胞来源于Ascl 1+祖细胞/OPC，并且Ascl 1是适当髓鞘再生所必需的。总之，我们的研究结果表明，Ascl 1功能调节多个步骤的OPC发展在出生后的大脑和响应脱髓鞘的侮辱。
Oligodendrocytes are the myelin-forming cells of the CNS. They differentiate from oligodendrocyte precursor cells (OPCs) that are produced from progenitors throughout life but more actively during the neonatal period and in response to demyelinating insults. An accurate regulation of oligodendrogenesis is required to generate oligodendrocytes during these developmental or repair processes. We hypothesized that this regulation implicates transcription factors, which are expressed by OPCs and/or their progenitors. Ascl1/Mash1 is a proneural transcription factor previously implicated in embryonic oligodendrogenesis and operating in genetic interaction with Olig2, an essential transcriptional regulator in oligodendrocyte development. Herein, we have investigated the contribution of Ascl1 to oligodendrocyte development and remyelination in the postnatal cortex. During the neonatal period, Ascl1 expression was detected in progenitors of the cortical subventricular zone and in cortical OPCs. Different genetic approaches to delete Ascl1 in cortical progenitors or OPCs reduced neonatal oligodendrogenesis, showing that Ascl1 positively regulated both OPC specification from subventricular zone progenitors as well as the balance between OPC differentiation and proliferation. Examination of remyelination processes, both in the mouse model for focal demyelination of the corpus callosum and in multiple sclerosis lesions in humans, indicated that Ascl1 activity was upregulated along with increased oligodendrogenesis observed in remyelinating lesions. Additional genetic evidence indicated that remyelinating oligodendrocytes derived from Ascl1+ progenitors/OPCs and that Ascl1 was required for proper remyelination. Together, our results show that Ascl1 function modulates multiplesteps of OPC development in the postnatal brain and in response to demyelinating insults.