Understanding the molecular mechanisms of Wnt and Notch signalling during embryonic development

About the Project

This project uses cutting-edge 3D gastruloid models to reveal how the integration of Wnt and Notch (Wntch) signalling pathways drives cell fate decisions in the early mammalian embryo. The student will uncover how Wntch controls cell fate and axial development by combining live quantitative imaging, engineered reporter lines, and precise pathway perturbations.

Project background

This project is an exciting opportunity for a motivated and talented student to contribute to new understanding of the cellular decision mechanisms that control cell fate in the early mammalian embryo.

During embryonic development, the embryo needs to convert a mass of identical cells into an organism with multiple axes of symmetry (anteroposterior, dorsoventral, mediolateral). Traditional approaches using forward and reverse genetics in animal models have elucidated many of the signals that specify these processes, however we still don’t fully understand the mechanisms that the embryo uses to integrate both mechanical and chemical signals over time, and how these impact cell fate allocation and morphogenesis.

To get a better understanding of these processes, this project will take an innovative in vitro organoid approach using gastruloids as an experimental system. Gastruloids are 3D aggregates of mouse embryonic stem cells that mimic many embryonic patterning events in culture, including the development of all three orthogonal embryonic axes. The highly-controlled and scalable nature of gastruloids provides the means to access, observe and quantify the unfolding of early developmental patterning in detail.

The successful applicant will utilise gastruloids to uncover how Wnt and Notch interact to control cell fate during early cell fate specification. They will use quantitative microscopy of fixed and live gastruloids, following reporter and protein dynamics in real time, assessing how specific inputs alter cell fate. The supervisory team will provide training and support in all relevant techniques.

Project Structure

In the first year, the student will learn all aspects of embryonic stem cell and gastruloid culture, as well as our advanced imaging techniques and analysis pipelines. As this transitions into the second year, the student will begin perturbations of Notch and Wnt signalling in reporter lines, and lines harbouring mutations in key Notch signalling components. Throughout the first and second year, the student will be generating new tools to visualise Notch and Wnt signalling in gastruloids, coupled with reporters of specific germ-layer markers. The latter parts of the second year into the third year will allow the student to explore the implications of their data, developing their independence in research, and consolidating the data they will have gathered. Their thesis writing will take up much of the last few months of their final year.

This project is ideally suited to a highly-motivated student who has an interest in embryonic stem cells, mammalian development, cell signalling, and quantitative approaches. The successful candidate should have, or expect to have, an Honours Degree at 2.1 or above (or equivalent) in a relevant biological sciences subject.

Candidates whose first language is not English should have an IELTS score of 6.5 or equivalent.

The successful applicant will be expected to provide the funding for tuition fees, living expenses, and attendance at conferences.

A research bench fee of £20,000 p.a. will be levied as a contribution to laboratory consumables, specific chemically-defined media and supplements, research facility access, and RNAseq.

There is NO institutional funding attached to this project. Details of costs can be found on the University website.