Sirt1 contributes critically to the redox-dependent fate of neural progenitors
Sirt1 contributes critically to the redox-dependent fate of neural progenitors
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DOI：
10.1038/ncb1700
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发表时间：
2008-04-01
影响因子：
21.3
通讯作者：
Aktas, Orhan
中科院分区：
文献类型：
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作者：
Prozorovski, Timour;Schulze-Topphoff, Ulf;Aktas, Orhan
响应于神经元损伤而激活的修复过程，无论是炎症性、缺血性、代谢性、创伤性还是其他原因，其特征在于不能补充神经元和星形胶质细胞增生。然而，对潜在的分子途径知之甚少。在这里，我们发现，在不同的大脑病理中发现的氧化还原状态的微妙变化，通过组蛋白去乙酰化酶（HDAC）Sirt1调节小鼠神经祖细胞（NPC）的命运。Sirt1的轻度氧化或直接激活抑制NPC的增殖，并以神经元谱系为代价将其分化为星形胶质细胞谱系，而还原条件具有相反的效果。在体外和体内氧化条件下，Sirt1在NPC中上调，与转录因子Hes 1结合，随后抑制促神经元Mash 1。子宫内shRNA介导的NPC中Sirt1的敲低阻止了氧化介导的神经发生抑制，并导致体内Mash1上调。我们的研究结果提供了一个未知的代谢总开关，决定神经祖细胞的命运的证据。
Repair processes that are activated in response to neuronal injury, be it inflammatory, ischaemic, metabolic, traumatic or other cause, are characterized by a failure to replenish neurons and by astrogliosis. The underlying molecular pathways, however, are poorly understood. Here, we show that subtle alterations of the redox state, found in different brain pathologies, regulate the fate of mouse neural progenitor cells ( NPCs) through the histone deacetylase ( HDAC) Sirt1. Mild oxidation or direct activation of Sirt1 suppressed proliferation of NPCs and directed their differentiation towards the astroglial lineage at the expense of the neuronal lineage, whereas reducing conditions had the opposite effect. Under oxidative conditions in vitro and in vivo, Sirt1 was upregulated in NPCs, bound to the transcription factor Hes1 and subsequently inhibited pro-neuronal Mash1. In utero shRNA-mediated knockdown of Sirt1 in NPCs prevented oxidation-mediated suppression of neurogenesis and caused upregulation of Mash1 in vivo. Our results provide evidence for an as yet unknown metabolic master switch that determines the fate of neural progenitors.