DiMeN Doctoral Training Partnership: Building functional epithelial tissues: coordinating planar po

In developing epithelial tissues, multiple mechanisms exist to orient cells within the plane of the tissue. Such ‘planar cell polarity’ (PCP) ensures that tissue growth, shape and structure are properly organised. PCP defects play a role in incomplete development such as failed neural tube closure and cleft palette and pathologies such as epithelial cancers. Intriguingly, both secreted morphogens and mechanical forces have been implicated as orienting cues for planar polarisation. The study of cell orientation thus provides a system for dissecting the interplay between chemical and mechanical signals. There is emerging evidence that errors in these mechanical signals occur in tissue disease, for example stroke, atherosclerosis and pulmonary fibrosis. Drosophila provides an ideal model system for dissecting these mechanisms, since it is highly amenable to genetic manipulation and has easily accessible simple epithelial tissues suitable for live imaging.

We will integrate cutting-edge genetic tools, advanced 4D fast live imaging and computational modelling in an iterative manner to: (i) explore how mechanical forces influence patterning and polarity; (ii) understand how cell division modulates tissue mechanics and coordinated cell polarity; and (iii) develop rigorous mathematical approaches to incorporate pattern and proliferation within existing modelling frameworks for epithelial morphogenesis.

Detailed spatiotemporal quantitative data concerning cell shape, cell division, patterning and in vivo cell tension in developing Drosophila tissues will be generated using the recently acquired Bateson Centre light sheet microscope, combined with genetically modified fly strains expressing fluorescently-tagged proteins and FRET-based tension sensors, under normal and abnormal conditions. Computational models will be implemented within the open source C++ library, Chaste (www.cs.ox.ac.uk/chaste), developed by the second supervisor and colleagues, which provides a framework for simulating vertex models of epithelial cell sheets. We will explore different assumptions about cell division and rearrangements within this consistent framework and validate model predictions against experimental observations.

Only with the advent of fast 4D live imaging, combined with genetically encoded fluorescent sensors and sophisticated computational modelling tools, is it now possible to make major advances in understanding epithelial tissue dynamics at a quantitative systems level. High-level experimental data will be used to validate and constrain computational models, which will further our understanding of the interplay between planar polarity and mechanobiology allowing us to gain a much deeper understanding of how tissue pattering and mechanics contribute to tissue development.

Funding Notes

This studentship is part of the MRC Discovery Medicine North (DiMeN) partnership and is funded for 3.5 years. Including the following financial support:

• Tax-free maintenance grant at the national UK Research Council rate
• Full payment of tuition fees at the standard UK/EU rate
• Research training support grant (RTSG)
• Travel allowance for attendance at UK and international meetings
• Opportunity to apply for Flexible Funds for further training and development