Dnmt1-dependent Chk1 pathway suppression is protective against neuron division
Dnmt1-dependent Chk1 pathway suppression is protective against neuron division
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DOI：
10.1242/dev.154013
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发表时间：
2017-09
期刊：
影响因子：
4.6
通讯作者：
M. Oshikawa;Kei Okada;H. Tabata;K. Nagata;I. Ajioka
中科院分区：
文献类型：
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作者：
M. Oshikawa;Kei Okada;H. Tabata;K. Nagata;I. Ajioka
即使在病理情况下，神经元分化和细胞周期退出也是紧密协调的。当病理神经元重新进入细胞周期并进入S期时，它们经历细胞死亡而不是分裂。然而，有丝分裂抵抗的机制大多是未知的。在这里，我们发现小鼠有丝分裂后神经元中视网膜母细胞瘤（Rb）家族蛋白（Rb， p107和p130）的急性失活导致细胞在s期进展后死亡。检查点激酶1 （Chk1）通路在S期激活可防止细胞死亡，并允许经历急性Rb家族失活、氧糖剥夺（OGD）或体内缺氧缺血的皮质神经元分裂。在神经发生过程中，皮质神经元受到DNA甲基转移酶Dnmt1的保护，不受s期Chk1通路的激活，并在s期进展后发生细胞死亡。我们的研究结果表明，Chk1通路的激活超越了有丝分裂的保护措施，并使神经元分化与有丝分裂抵抗分离。摘要：通过Rb三敲除小鼠模型，研究表明，S期Chk1通路激活可防止细胞死亡，并克服病理性缺氧和分化神经元的有丝分裂阻力。
Neuronal differentiation and cell-cycle exit are tightly coordinated, even in pathological situations. When pathological neurons re-enter the cell cycle and progress through the S phase, they undergo cell death instead of division. However, the mechanisms underlying mitotic resistance are mostly unknown. Here, we have found that acute inactivation of retinoblastoma (Rb) family proteins (Rb, p107 and p130) in mouse postmitotic neurons leads to cell death after S-phase progression. Checkpoint kinase 1 (Chk1) pathway activation during the S phase prevented the cell death, and allowed the division of cortical neurons that had undergone acute Rb family inactivation, oxygen-glucose deprivation (OGD) or in vivo hypoxia-ischemia. During neurogenesis, cortical neurons became protected from S-phase Chk1 pathway activation by the DNA methyltransferase Dnmt1, and underwent cell death after S-phase progression. Our results indicate that Chk1 pathway activation overrides mitotic safeguards and uncouples neuronal differentiation from mitotic resistance. Summary: Using a Rb triple knockout mouse model, Chk1 pathway activation during S phase is shown to prevent cell death and override the mitotic resistance of pathological hypoxic and differentiating neurons.