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Visualizing the metazoan proliferation-quiescence decision in vivo.

ABSTRACT: Cell proliferation and quiescence are intimately coordinated during metazoan development. Here, we adapt a cyclin-dependent kinase (CDK) sensor to uncouple these key events of the cell cycle in Caenorhabditis elegans and zebrafish through live-cell imaging. The CDK sensor consists of a fluorescently tagged CDK substrate that steadily translocates from the nucleus to the cytoplasm in response to increasing CDK activity and consequent sensor phosphorylation. We show that the CDK sensor can distinguish cycling cells in G1 from quiescent cells in G0, revealing a possible commitment point and a cryptic stochasticity in an otherwise invariant C. elegans cell lineage. Finally, we derive a predictive model of future proliferation behavior in C. elegans based on a snapshot of CDK activity in newly born cells. Thus, we introduce a live-cell imaging tool to facilitate in vivo studies of cell-cycle control in a wide-range of developmental contexts.

SUBMITTER: Adikes RC

PROVIDER: S-EPMC7880687 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Visualizing the metazoan proliferation-quiescence decision in vivo.

Adikes Rebecca C RC Kohrman Abraham Q AQ Martinez Michael A Q MAQ Palmisano Nicholas J NJ Smith Jayson J JJ Medwig-Kinney Taylor N TN Min Mingwei M Sallee Maria D MD Ahmed Ononnah B OB Kim Nuri N Liu Simeiyun S Morabito Robert D RD Weeks Nicholas N Zhao Qinyun Q Zhang Wan W Feldman Jessica L JL Barkoulas Michalis M Pani Ariel M AM Spencer Sabrina L SL Martin Benjamin L BL Matus David Q DQ

eLife 20201222

Cell proliferation and quiescence are intimately coordinated during metazoan development. Here, we adapt a cyclin-dependent kinase (CDK) sensor to uncouple these key events of the cell cycle in <i>Caenorhabditis elegans</i> and zebrafish through live-cell imaging. The CDK sensor consists of a fluorescently tagged CDK substrate that steadily translocates from the nucleus to the cytoplasm in response to increasing CDK activity and consequent sensor phosphorylation. We show that the CDK sensor can ...[more]

PMID: 33350383

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Project description:Heldt2018 - Proliferation-quiescence decision in response to DNA damage This model is described in the article: A comprehensive model for the proliferation-quiescence decision in response to endogenous DNA damage in human cells. Heldt FS, Barr AR, Cooper S, Bakal C, Novák B. Proc. Natl. Acad. Sci. U.S.A. 2018 Feb; : Abstract: Human cells that suffer mild DNA damage can enter a reversible state of growth arrest known as quiescence. This decision to temporarily exit the cell cycle is essential to prevent the propagation of mutations, and most cancer cells harbor defects in the underlying control system. Here we present a mechanistic mathematical model to study the proliferation-quiescence decision in nontransformed human cells. We show that two bistable switches, the restriction point (RP) and the G1/S transition, mediate this decision by integrating DNA damage and mitogen signals. In particular, our data suggest that the cyclin-dependent kinase inhibitor p21 (Cip1/Waf1), which is expressed in response to DNA damage, promotes quiescence by blocking positive feedback loops that facilitate G1 progression downstream of serum stimulation. Intriguingly, cells exploit bistability in the RP to convert graded p21 and mitogen signals into an all-or-nothing cell-cycle response. The same mechanism creates a window of opportunity where G1 cells that have passed the RP can revert to quiescence if exposed to DNA damage. We present experimental evidence that cells gradually lose this ability to revert to quiescence as they progress through G1 and that the onset of rapid p21 degradation at the G1/S transition prevents this response altogether, insulating S phase from mild, endogenous DNA damage. Thus, two bistable switches conspire in the early cell cycle to provide both sensitivity and robustness to external stimuli. This model is hosted on BioModels Database and identified by: MODEL1703030000. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Visualizing the metazoan proliferation-quiescence decision in vivo.

Publications

Visualizing the metazoan proliferation-quiescence decision in vivo.

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