Hubatsch, Lars; (2018) Interplay between cell size and cell polarity. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cell polarity is a fundamental phenomenon underlying processes such as asymmetric cell division, tissue homeostasis and directed cell migration. In metazoans, the conserved PAR (-titioning defective) protein network polarizes cells with different shapes and sizes. Here, I investigate whether cell size influences the polarity pattern set up by the PARs. PAR polarity is typically achieved by localizing different sets of antagonizing proteins to opposing membrane domains. Antagonism ensures that mixing of the two species is restricted to a region between the two domains. Theoretically, this can be described using reaction-diffusion models, in which abstract biochemical agents are able to exchange between membrane and cytosol, and are subjected to cytosolic and membrane diffusion. Under suitable conditions, their interactions give rise to a stable pattern. In such a system, the interplay between diffusion and reaction rates determines the pattern by setting key length scales, for example, the extent of the boundary region between the two opposing domains. Using computer simulations, I first show that current reaction-diffusion models fail to adapt such pattern length scales to cell size. Second, this results in pattern breakdown below a certain minimum size, producing completely uniform protein distributions across the membrane. We term this size critical polarizable system size (CPSS). To test the first prediction - failure to adapt to cell size - I measured kinetic parameters and the resulting pattern length scales in differently sized cells, using the early C. elegans embryo as a model. The results suggest a moderate, if any, adaptation, prompting me to examine the second prediction - failure to maintain polarity at small sizes. By combining novel computational methods for 3D membrane reconstruction with cell size mutants, I then show that small cells are indeed unable to maintain polarity, thus establishing a lower size limit for polarity in vivo.

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