Dr Martin Baron, Prof Mike White
Applications accepted all year round
Self-Funded PhD Students Only
About the Project
This project will investigate the roles that competing fluxes through endocytic trafficking networks play to modulate developmental signalling outputs during cell fate decision making. Using the Drosophila Notch signal as a model system we will combine experimental and mathematical modelling to investigate how endocytic network parameters influence signalling levels, and use the models derived to understand the link between genotype and developmental phenotype for a range of Notch mutations that affect its trafficking.
Endocytosis is a central organiser of cellular physiology and is the means by which cells sample and respond to their external environments. The endocytosis of signalling receptors from the cell surface to internal organelles plays a key role in shaping cell fate decisions during developmental patterning. Endocytosis can act negatively on signalling by removing receptors from access to external ligands and by directing them to lysosomal degradation. On the other hand endocytic trafficking can also have a positive role by relocating receptors to internal organelle membrane domains where signalling-competent platforms can assemble to initiate or prolong receptor activity. The flux balance of traffic through different endocytic routes and destinations therefore plays important roles in the summation of positive and negative inputs to tune overall signalling levels. However the underlying complexities of the interconnected networks cannot be readily understood without a combined experimental and computational approach.
This project will investigate these dynamic regulatory processes using fluorescent protein-tagged constructs of Notch and endosomal components, generated by CRISPR gene editing, to live image Notch localisation and endosomal transport, and luciferase reporter constructs to quantify signalling outputs. We will combine experimental observations with mathematical modelling and numerical simulation to understand how genetic and environmental induced changes in the underlying stochastic dynamics of the endosomal transport and maturation processes affect Notch signalling outcomes and derive models explaining genotype/phenotype linkages.
Funding Notes
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with experience in Drosophila or with an interest in cell signalling or protein trafficking are encouraged to apply.
This project has a Band 2 fee. Details of our different fee bands can be found on our website (https://www.bmh.manchester.ac.uk/study/research/fees/). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/).
Informal enquiries may be made directly to the primary supervisor.
References
Shimizu H, Wilkin MB, Woodcock SA, Bonfini A, Hung Y, Mazaleyrat S, Baron M. (2017). The Drosophila ZO-1 protein Polychaetoid suppresses Deltex-regulated Notch activity to modulate germline stem cell niche formation. Open Biol. 7 pii: 160322.
Bonfini A, Wilkin MB, Baron M. (2015) Reversible regulation of stem cell niche size associated with dietary control of Notch signalling. BMC Dev Biol. 31;15:8.
Shimizu H, Woodcock SA, Wilkin MB, Trubenová B, Monk NA, Baron M. (2014) Compensatory flux changes within an endocytic trafficking network maintain thermal robustness of Notch signaling. Cell 157:1160-74.