MRC DTP: Quantitative approaches to cell polarity regulation

This PhD project will combine mathematical modelling and experimental approaches in order to understand the spatiotemporal dynamics that regulate asymmetric cell division. Asymmetric cell division is a fundamental process that generates cellular diversity. Moreover, stem cells in higher organisms can polarise and segregate evolutionarily conserved fate determinants unequally to the resulting daughter cells that then undergo different developmental programs. Perturbation of asymmetric cell division causes tumour-like growth in flies and has also been linked to poor prognosis for breast cancer patients. Whilst cell polarity has been intensively studied in cells that are largely non-dividing, our understanding of how polarity and cell division are coordinated in stem cells is much less clear. Although the key molecules regulating this process have been identified, we do not understand the precise molecular logic of how opposing membrane domains, a key feature of polarity, are established.

To address this question, the Januschke lab has developed a suite of cutting-edge tools that allow imaging and perturbation of highly proliferative Drosophila neural stem cells, yielding complex spatiotemporal datasets that allow us to visualise the dynamics of key regulators of polarity and cell division. The aim of this project is to develop mathematical and computational tools that can be used to understand features of these datasets, test hypotheses and aid in the design of future experiments. The mathematical model will comprise a system of coupled nonlinear partial differential equations that describe the dynamics of key kinases and their substrates. The model, which will be calibrated using imaging data from the Januschke lab, will be used to explore in silico how variations in molecular circuitry affect spatial localisation and hence polarity. The ultimate aim is to uncover the critical regulatory mechanisms that impose polarity during asymmetric stem cell division in order to prevent stem cell lineages from derailment into tumour-like growth.