University of Dundee

MRC DTP 4 Year PhD Programme: Interrogating the interdependence of the cell cycle and the segmentation clock

This project is offered as part of the University of Dundee 4-year MRC DTP Programme “Quantitative and Interdisciplinary approaches to biomedical science”. This PhD programme brings together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science.  The outstanding biomedical research at the University of Dundee was recognised by its very high rankings in REF 2014, with Dundee rated as the top University for Biological Sciences in the UK.  A wide range of projects are available within this programme crossing exceptional strengths in four key areas: Infection and Disease; Responses to Cellular Stresses; Development, Stem Cells and Neurobiology; and Big Data and Translation.  All students on this programme will receive training in computational biology, mathematical biology and statistics to equip with the quantitative skills in tackling complex biological questions.  In the 1st year, students will carry out 3 rotation projects prior to selection of the final PhD project.

This interdisciplinary project will combine mathematicaland experimental approachesin order to investigate how perturbations to the molecular machinery of the segmentation clock affects coupling to the cell cycle. In humans, defects in segmentation lead to congenital scoliosis, a disease with an infantmortality rate of 50% that comprises many vertebral skeletal pathologies including the family of spondylocostal dysostoses.The segmentation clock is a multicellular oscillator that resides in the presomitic mesoderm(PSM)and regulates the segmentation of the vertebrate embryo. PSM tissue is comprised of a population of PSM cells, each of which hasautonomous oscillator. Intercellular coupling, mediated by the Notch signaling pathway, results in the emergence of synchronized oscillations at the tissue scale.We have recently established thatcell cycle kinasesmodulateNotch signaling and used computational modeling to investigate the functionalrole of thisinteractionin PSM tissue. Moreover, we have recently developed an iPS-derived PSM tissue culture system that has a real-time reporter for the segmentation clock. The major aim of this project is to use the new system to investigate how perturbations to both the cell cycle and segmentation clock affect the cross talk between the cell cycle and the segmentation clock.

We will experimentally perturb the segmentation clock and the cell cycle and measure the effect on the segmentation clock reporter. We will use phase reconstruction methods to infer the clock frequency and develop computational/mathematical models that allow us to understand the experimental data.

Recent work from the lab can be found in the following references:

Cell cycle regulation of oscillations yields coupling of growth and form in a computational model of the presomitic mesoderm PJ Murray, FA Carrieri, JK Dale Journal of Theoretical Biology

CDK 1 and CDK 2 regulate NICD 1 turnover and the periodicity of the segmentation clock FA Carrieri, PJ Murray, D Ditsova, MA Ferris, P Davies, JKDaleEMBO reports, e46436

The effect of Rosovitine on mPSM explants: a real time analysis PJ Murray, KJ Dale, LJ Morales, CSL BaileybioRxiv, 789446

A balance of positive and negative regulators determines the pace of the segmentation clock G Wiedermann, RA Bone, JC Silva, M Bjorklund, PJ Murray, JK DaleElife 4, e05842