This interdisciplinary PhD project will identify how Notch and the cell cycle regulate growth and form in the developing vertebrate embryo by experimentally testing and refining a computational model that we have recently developed. Notch plays a fundamental role in the regulation of many aspects of embryo development (e.g. , neurogenesis, vascular development). Moreover, it is one of the most activated pathways in some cancers. The overarching aim of this project is to test the hypothesis that the distribution of PSM cells in different phases of the cell cycle regulates the emergent segmentation clock frequency in a Notch dependent manner couple growth and pattern formation in the developing vertebrate embryo. To address this aim, we will use to simultaneously measure segmentation clock and cell cycle phases in derived mesoderm (PSM) cells that contain a segmentation clock reporter. We will consider different configurations of the PSM cells (e.g. isolated, monolayer cultures, 3D cultures) and investigate whether and how Notch -mediated interdependence between the segmentation clock and the cell cycle facilitates the emergence of a cell cycle-dependent, tissue-scale oscillator frequency. The experimental results will be used to further refine the existing mathematical models which in turn we will to explore system in silico.
Recent work from the lab can be found in the following references:
Carrieri, F.A., Murray, P.J., Ditsova, D., Ferris, M.A., Davies, P., Dale, J.K (2019) CDK1 and CDK2 regulate NICD1 turnover and periodicity of the segmentation clock. EMBO Reports. 20, 4, p. 1-22 22 p., e46436 /10.15252/embr.201846436 PMID 31267714 Read Article
Murray, P., Carrieri, F.A., Dale, J.K. (2019) Cell cycle regulation of oscillations yields coupling of growth and from in a computational model of the mesoderm. Journal of Theoretical Biology. /10.1016/j.jtbi.2019.05.006 PMID 31121170 Read Article
, G., Bone, R. A., Dale, J. K., et al. (2015) A balance of positive and negative regulators determines the pace of the segmentation clock. Elife 4: e05842. /10.7554/eLife.05842 PMCID 4601006 PMID 26357015 Read Article