Molecular feedback and self-organisation in the PAR polarity network

PhD Thesis, Tom Bland (2022)

Abstract

Polarisation of cells by the PAR network bears hallmarks of a self-organising reaction-diffusion network, comprising of two sets of proteins which stably segregate into mutually exclusive membrane-associated domains. A number of nonlinear behaviours, including antagonistic feedback interactions, protein oligomerisation and positive feedback reactions have been proposed to contribute to the maintenance of this stable polarised state, but we lack sufficient insight into the quantitative nature of these interactions to fully understand their contribution to polarity. Furthermore, recent work reveals that PAR protein patterns display striking and unexpected robustness to breakages in this reaction network, implying the existence of additional feedback reactions that we are yet to fully account for.

Through quantitative imaging, gene editing, in vitro biochemistry, and mathematical modelling, I have taken an interdisciplinary approach to study the molecular circuitry of feedback reactions in the C. elegans PAR network. Focussing on the posterior PAR subnetwork, my work reveals a novel role for the RING-finger domain of PAR-2 in facilitating concentration-dependent protein dimerisation, which drives stable membrane association and contributes to positive-feedback driven polarity.

Code availability

All code is available here

Publications

Some of this work has been published in the following articles:

• Optimized dimerization of the PAR-2 RING domain drives cooperative and selective membrane recruitment for robust feedback-driven cell polarization. BioRxiv (2023). Preprint

• SAIBR : A simple, platform-independent method for spectral autofluorescence correction. Development (2022).