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CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock.


ABSTRACT: All vertebrates share a segmented body axis. Segments form from the rostral end of the presomitic mesoderm (PSM) with a periodicity that is regulated by the segmentation clock. The segmentation clock is a molecular oscillator that exhibits dynamic clock gene expression across the PSM with a periodicity that matches somite formation. Notch signalling is crucial to this process. Altering Notch intracellular domain (NICD) stability affects both the clock period and somite size. However, the mechanism by which NICD stability is regulated in this context is unclear. We identified a highly conserved site crucial for NICD recognition by the SCF E3 ligase, which targets NICD for degradation. We demonstrate both CDK1 and CDK2 can phosphorylate NICD in the domain where this crucial residue lies and that NICD levels vary in a cell cycle-dependent manner. Inhibiting CDK1 or CDK2 activity increases NICD levels both in vitro and in vivo, leading to a delay of clock gene oscillations and an increase in somite size.

SUBMITTER: Carrieri FA 

PROVIDER: S-EPMC6607002 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock.

Carrieri Francesca Anna FA   Murray Philip J PJ   Ditsova Dimitrinka D   Ferris Margaret Ashley MA   Davies Paul P   Dale Jacqueline Kim JK  

EMBO reports 20190417 7


All vertebrates share a segmented body axis. Segments form from the rostral end of the presomitic mesoderm (PSM) with a periodicity that is regulated by the segmentation clock. The segmentation clock is a molecular oscillator that exhibits dynamic clock gene expression across the PSM with a periodicity that matches somite formation. Notch signalling is crucial to this process. Altering Notch intracellular domain (NICD) stability affects both the clock period and somite size. However, the mechani  ...[more]

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