Cell cycle and cell death regulation of neural progenitor cells in the 5-azacytidine (5AzC)-treated developing fetal brain
Cell cycle and cell death regulation of neural progenitor cells in the 5-azacytidine (5AzC)-treated developing fetal brain
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DOI：
10.1016/j.expneurol.2005.11.024
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发表时间：
2006-03
影响因子：
5.3
通讯作者：
M. Ueno;K. Katayama;H. Yamauchi;H. Nakayama;K. Doi
中科院分区：
文献类型：
--
作者：
M. Ueno;K. Katayama;H. Yamauchi;H. Nakayama;K. Doi
在发育中的大脑中，神经前体细胞容易受到包括DNA损伤在内的许多外部压力的影响。我们用DNA去甲基化和损伤剂5-氮杂胞苷(5-azacytidine，5AzC)处理孕鼠，观察胎脑的细胞反应，重点是细胞增殖和细胞死亡的调节。5AzC首先诱导有丝分裂异常的细胞聚集，G2期聚集，然后诱导神经前体细胞凋亡。大部分凋亡细胞处于G1期。细胞周期转换研究表明，G2/M期进程被阻断，之后细胞进入G1期或发生凋亡。免疫印迹和DNA芯片分析显示，DNA损伤应答的关键因子P53及其部分靶基因的表达增加。在5AzC处理的p53基因缺陷小鼠胎脑中，虽然诱导了G2/M期的积聚，但没有发生细胞凋亡。这些结果表明，在发育中的大脑中，细胞凋亡是依赖于P53的，但另一种机制控制着G2/M检查点。G2/M调节因子CDc2通过G2/M的积累被去磷酸化激活，提示细胞加速进入有丝分裂，导致出现异常有丝分裂的细胞积累。此外，一些细胞可能已经死于有丝分裂灾难。在整个大脑发育过程中，各种细胞周期和细胞死亡调节机制为神经前体细胞提供了防御DNA损伤的选择。
In the developing brain, neural progenitor cells are susceptible to many extrinsic stresses, including DNA damage. We treated pregnant rats with 5-azacytidine (5AzC), a DNA demethylating and damaging agent, to investigate the cellular responses of the fetal brain, focusing on the regulation of proliferation and cell death. 5AzC first induced the accumulation of cells in abnormal mitosis, G2-phase accumulation, and then apoptosis of the neural progenitor cells. Most of the apoptotic cells were in G1 phase. Cell cycle transition studies suggested that G2/M progression was blocked, after which the cells moved to G1 phase or underwent apoptosis. p53, a key factor for response to DNA damage, and some of its target genes showed increased expression in Western blot and DNA microarray analyses. In 5AzC-treated fetal brains of p53-deficient mice, apoptosis did not occur, although G2/M accumulation was induced. These results suggest that, in the developing brain, apoptosis is p53-dependent but that another mechanism governs the G2/M checkpoint. The G2/M regulator, Cdc2, was activated by dephosphorylation through G2/M accumulation, suggesting accelerated entry into mitosis leading to accumulation of cells showing abnormal mitosis. Furthermore, some cells may have died due to mitotic catastrophe. Throughout brain development, various cell cycle and cell death regulation mechanisms provide neural progenitor cells with options for defense from DNA damage.