Latest research from Professor Kim Dale and collaborators has uncovered further knowledge into the developmental segmentation process which may also impact on our understanding of diseases such as cancer. This research was published this week in EMBO Reports.
Professor Dale explained, "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. Notch signalling is crucial to this process, since we have previously shown that in the absence of Notch signalling, the segmentation clock stops and no somites form. Altering Notch intracellular domain (NICD) stability affects both the clock period and somite size. Moreover, aberrant NICD turnover contributes to numerous cancers and diseases. Despite the multiple impacts of NICD turnover in both development and disease, the molecular mechanism regulating this turnover remains largely uncharacterised."
This interdisciplinary project was the work of PhD student Francesca Anna Carrieri from Professor Dale’s lab in the division of Cell and Developmental Biology. Alongside researchers from the Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC PPU) in the School, the Department of Mathematics at Dundee and Washington University School of Medicine they identified a highly conserved site crucial for NICD recognition by the SCF E3 ligase, which targets NICD for degradation. They demonstrated for the first time that 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. Lastly, they showed that inhibiting CDK1 or CDK2 activity increases NICD levels both in vitro and in vivo, leading to a delay in the segmentation clock and an increase in somite size.
"Our novel finding of a reciprocal auto-regulatory role between the cell cycle regulated CDKs, CDK1 and CDK2, and NICD turnover has potentially great relevance to the developmental biology community and may provide additional insight into disease/cancer contexts where this autoregulation may have gone awry," Professor Dale concluded.