Oshikawa Mio, Okada Kei, Tabata Hidenori, Nagata Koh-Ichi, Ajioka Itsuki
Center for Brain Integration Research (CBIR), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan.
Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai Aichi 480-0392, Japan.
Development. 2017 Sep 15;144(18):3303-3314. doi: 10.1242/dev.154013.
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 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.
即使在病理情况下，神经元分化和细胞周期退出也紧密协调。当病理性神经元重新进入细胞周期并进入S期时，它们会发生细胞死亡而非分裂。然而，有丝分裂抗性的潜在机制大多未知。在此，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）的急性失活会导致S期进展后细胞死亡。S期期间检查点激酶1（Chk1）途径的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）或缺氧缺血的皮质神经元进行分裂。在神经发生过程中，DNA甲基转移酶Dnmt1使皮质神经元免受S期Chk1途径激活的影响，并且在S期进展后发生细胞死亡。我们的结果表明，Chk1途径激活超越了有丝分裂保障机制，并使神经元分化与有丝分裂抗性脱钩。
