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Resources » Paper

Portegijs, Vincent et al. (2021) International Worm Meeting "Multiple levels of regulation ensure robust cell cycle exit during C. elegans vulva formation"

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  • Overview

    Status:
    Publication type:
    Meeting_abstract
    WormBase ID:
    WBPaper00062830

    Portegijs, Vincent, Godfrey, Molly, & Van den Heuvel, Sander (2021). Multiple levels of regulation ensure robust cell cycle exit during C. elegans vulva formation presented in International Worm Meeting. Unpublished information; cite only with author permission.

    Regulated cell cycle withdrawal is crucial for cell differentiation and tissue homeostasis, with impaired cell cycle exit leading to hyperplasia, a hallmark of cancer. The reproducible pattern of cell proliferation and differentiation in C. elegans provides an excellent model to study the regulatory pathways that control cell cycle arrest. Using tissue-specific gene knockout combined with lineage tracing, we explored whether known cell cycle inhibitors and tumor suppressor genes regulate cell cycle exit of the epidermal vulva precursor cells (VPCs). Lineage-specific knockout of cki-1, the main C. elegans CIP/KIP cell-cycle inhibitor, resulted in a surprisingly weak extra vulval cell division phenotype. We found that a second CIP/KIP inhibitor, cki-2, becomes transcriptionally upregulated in these cki-1 knockout animals. Simultaneous knockout of both CKIs substantially increased the number of extra vulva cells. In addition to cki-2, we discovered that cep-1 p53 and daf-3 Smad4 contribute to proper cell cycle arrest of cki-1 knockout vulval cells. Genetic analyses support a model in which these transcriptional regulators act upstream of cki-2 to promote cki-2 expression, which is critical only when cki-1 is absent. Furthermore, a forward genetic screen identified the HECT-domain ubiquitin ligase UBR-5 as another factor contributing to the timely VPC cell division arrest. The ubr-5 overproliferation phenotype was markedly enhanced when combined with cki-1 knockout, indicating that UBR-5 may act in parallel to CKI-1. Notably, all tested combinations of negative cell-cycle regulator knockout/knockdown resulted in limited increases in vulval cell numbers. Our data support that multiple redundant levels of regulation ensure remarkably robust control of cell cycle withdrawal of C. elegans vulval cells.

    Affiliation:
    - Utrecht University


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