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CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock.
EMBO Rep 2019; 20(7):e46436ER

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.

Authors+Show Affiliations

Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee, UK.Department of Mathematics, University of Dundee, Dundee, UK.Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee, UK.Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA.Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee, UK.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31267714

Citation

Carrieri, Francesca Anna, et al. "CDK1 and CDK2 Regulate NICD1 Turnover and the Periodicity of the Segmentation Clock." EMBO Reports, vol. 20, no. 7, 2019, pp. e46436.
Carrieri FA, Murray PJ, Ditsova D, et al. CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock. EMBO Rep. 2019;20(7):e46436.
Carrieri, F. A., Murray, P. J., Ditsova, D., Ferris, M. A., Davies, P., & Dale, J. K. (2019). CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock. EMBO Reports, 20(7), pp. e46436. doi:10.15252/embr.201846436.
Carrieri FA, et al. CDK1 and CDK2 Regulate NICD1 Turnover and the Periodicity of the Segmentation Clock. EMBO Rep. 2019;20(7):e46436. PubMed PMID: 31267714.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock. AU - Carrieri,Francesca Anna, AU - Murray,Philip J, AU - Ditsova,Dimitrinka, AU - Ferris,Margaret Ashley, AU - Davies,Paul, AU - Dale,Jacqueline Kim, Y1 - 2019/04/17/ PY - 2018/05/16/received PY - 2019/03/11/revised PY - 2019/03/26/accepted PY - 2019/7/4/entrez PY - 2019/7/4/pubmed PY - 2019/7/4/medline KW - FBXW7 KW - Notch KW - cell cycle KW - phosphorylation KW - somitogenesis SP - e46436 EP - e46436 JF - EMBO reports JO - EMBO Rep. VL - 20 IS - 7 N2 - 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. SN - 1469-3178 UR - https://www.unboundmedicine.com/medline/citation/31267714/CDK1_and_CDK2_regulate_NICD1_turnover_and_the_periodicity_of_the_segmentation_clock L2 - https://doi.org/10.15252/embr.201846436 DB - PRIME DP - Unbound Medicine ER -