Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation
Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation
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DOI：
10.1073/pnas.0800612105
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发表时间：
2008-10-07
影响因子：
11.1
通讯作者：
Horio, Yoshiyuki
中科院分区：
文献类型：
--
作者：
Hisahara, Shin;Chiba, Susumu;Horio, Yoshiyuki
神经前体细胞（NPC）在内在和外在的变化下分化为神经元、星形胶质细胞和少突胶质细胞。Notch信号维持未分化的NPC，但神经元分化的机制在很大程度上是未知的。我们发现，SIRT 1，NAD（+）依赖性组蛋白脱乙酰酶，调节神经元分化。SIRT 1在胚胎和成人NPC的细胞质中被发现，并在细胞核中短暂定位于分化刺激。SIRT 1在NPC转入分化条件后10 min内开始易位入核，停留在核中，然后在数小时后逐渐重新易位至细胞质。产生Tuj 1（+）神经元的神经球的数量被SIRT 1的药理学抑制剂、显性负SIRT 1和SIRT 1-siRNA显著减少，而SIRT 1的过表达（而不是胞质定位的突变体SIRT 1的过表达）增强了神经元分化并降低了Hes 1表达。SIRT 1-siRNA的表达损害神经元分化和NPCs迁移到胚胎脑皮质板。据报道，核受体辅阻遏物（N-CoR）可结合SIRT 1，促进神经元分化，并协同SIRT 1增加Tuj 1（+）神经元的数量，并且两者都结合分化NPC中的Hes 1启动子区域。Notch 1对Hes 1的反式激活作用可被SIRT 1和/或N-CoR抑制。我们的研究表明SIRT 1是Notch 1-Hes 1信号通路的抑制者，其瞬时易位入核可能在NPC的分化中起作用。
Neural precursor cells (NPCs) differentiate into neurons, astrocytes, and oligodendrocytes in response to intrinsic and extrinsic changes. Notch signals maintain undifferentiated NPCs, but the mechanisms underlying the neuronal differentiation are largely unknown. We show that SIRT1, an NAD(+)-dependent histone deacetylase, modulates neuronal differentiation. SIRT1 was found in the cytoplasm of embryonic and adult NPCs and was transiently localized in the nucleus in response to differentiation stimulus. SIRT1 started to translocate into the nucleus within 10 min after the transfer of NPCs into differentiation conditions, stayed in the nucleus, and then gradually retranslocated to the cytoplasm after several hours. The number of neurospheres that generated Tuj1(+) neurons was significantly decreased by pharmacological inhibitors of SIRT1, dominant-negative SIRT1 and SIRT1-siRNA, whereas overexpression of SIRT1, but not that of cytoplasm-localized mutant SIRT1, enhanced neuronal differentiation and decreased Hes1 expression. Expression of SIRT1-siRNA impaired neuronal differentiation and migration of NPCs into the cortical plate in the embryonic brain. Nuclear receptor corepressor (N-CoR), which has been reported to bind SIRT1, promoted neuronal differentiation and synergistically increased the number of Tuj1(+) neurons with SIRT1, and both bound the Hes1 promoter region in differentiating NPCs. Hes1 transactivation by Notch1 was inhibited by SIRT1 and/or N-CoR. Our study indicated that SIRT1 is a player of repressing Notch1-Hes1 signaling pathway, and its transient translocation into the nucleus may have a role in the differentiation of NPCs.