Dnmt1-dependent Chk1 pathway suppression is protective against neuron division
Mio Oshikawa1, Kei Okada1, Hidenori Tabata2
1Center for Brain Integration Research (CBIR), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan.
Abstract:
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.
Insights
Neuronal cell death occurs when neurons re-enter the cell cycle. Activating the Checkpoint kinase 1 (Chk1) pathway prevents this death, allowing neuronal division even after injury.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Neuronal differentiation and cell-cycle exit are tightly regulated processes.
- Pathological neurons that re-enter the cell cycle typically undergo cell death, but the mechanisms of this mitotic resistance are not fully understood.
Purpose of the Study:
- To investigate the mechanisms underlying mitotic resistance in postmitotic neurons.
- To determine the role of the retinoblastoma (Rb) protein family and the Checkpoint kinase 1 (Chk1) pathway in neuronal cell-cycle progression and survival.
Main Methods:
- Acute inactivation of Rb family proteins (Rb, p107, p130) in mouse postmitotic neurons.
- Induction of S-phase progression and subsequent cell death.
- Analysis of Chk1 pathway activation in response to Rb family inactivation, oxygen-glucose deprivation (OGD), and in vivo hypoxia-ischemia.
- Investigation of the role of DNA methyltransferase Dnmt1 in protecting cortical neurons during neurogenesis.
Main Results:
- Acute inactivation of Rb family proteins in postmitotic neurons led to cell death following S-phase progression.
- Activation of the Chk1 pathway during S phase prevented cell death and enabled cortical neuron division after Rb inactivation, OGD, or hypoxia-ischemia.
- During neurogenesis, cortical neurons are protected from S-phase Chk1 activation by Dnmt1, leading to cell death after S-phase progression.
Conclusions:
- Chk1 pathway activation can override intrinsic mitotic safeguards in neurons.
- The Chk1 pathway plays a critical role in determining neuronal fate after cell-cycle re-entry and injury.
- Understanding these mechanisms may offer therapeutic targets for neurological disorders involving neuronal loss.
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