NEUROG2 Drives Cell Cycle Exit of Neuronal Precursors by Specifically Repressing a Subset of Cyclins Acting at the G1 and S Phases of the Cell Cycle
NEUROG2 Drives Cell Cycle Exit of Neuronal Precursors by Specifically Repressing a Subset of Cyclins Acting at the G1 and S Phases of the Cell Cycle
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DOI：
10.1128/mcb.06745-11
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发表时间：
2012-07-01
影响因子：
5.3
通讯作者：
Bel-Vialar, Sophie
中科院分区：
文献类型：
--
作者：
Lacomme, Marine;Liaubet, Laurence;Bel-Vialar, Sophie
前神经元NEUROG2（neurogenin 2 [Ngn 2]）对于神经元定型、细胞周期退出和神经元分化是必不可少的。虽然NEUROG 2对神经元定向和分化的影响开始被阐明，但其在细胞周期退出中的作用仍然未知。因此，我们着手研究在脊髓神经发生过程中NEUROG 2诱导细胞周期阻滞的分子机制。我们开发了一种大规模的鸡胚胎策略，旨在寻找在NEUROG2表达开始时修饰的基因网络，从而确定了那些参与控制细胞周期的基因。NEUROG2激活导致作用于G（1）和S期的细胞周期调节因子亚组的快速减少，包括CCND1、CCNE1/2和CCNA2，但不包括CCND2。使用NEUROG2VP16和NEUROG2EnR分别作为组成型激活剂和抑制剂，表明NEUROG2间接抑制CCND1和CCNE2，但开启了CCNE2也被直接机制抑制的可能性。我们通过表型分析证明，这种快速抑制细胞周期蛋白阻止神经元前体进入S期，从而有利于细胞周期退出。我们还表明，细胞周期退出可以从神经元分化中解耦，并且在正常发育期间，NEUROG 2负责紧密协调这两个过程。
Proneural NEUROG2 (neurogenin 2 [Ngn2]) is essential for neuronal commitment, cell cycle withdrawal, and neuronal differentiation. Although NEUROG2's influence on neuronal commitment and differentiation is beginning to be clarified, its role in cell cycle withdrawal remains unknown. We therefore set out to investigate the molecular mechanisms by which NEUROG2 induces cell cycle arrest during spinal neurogenesis. We developed a large-scale chicken embryo strategy, designed to find gene networks modified at the onset of NEUROG2 expression, and thereby we identified those involved in controlling the cell cycle. NEUROG2 activation leads to a rapid decrease of a subset of cell cycle regulators acting at G(1) and S phases, including CCND1, CCNE1/2, and CCNA2 but not CCND2. The use of NEUROG2VP16 and NEUROG2EnR, acting as the constitutive activator and repressor, respectively, indicates that NEUROG2 indirectly represses CCND1 and CCNE2 but opens the possibility that CCNE2 is also repressed by a direct mechanism. We demonstrated by phenotypic analysis that this rapid repression of cyclins prevents S phase entry of neuronal precursors, thus favoring cell cycle exit. We also showed that cell cycle exit can be uncoupled from neuronal differentiation and that during normal development NEUROG2 is in charge of tightly coordinating these two processes.