Silva, E.; (2006) The role of tumour suppressor fat in the patterning and development of the Drosophila eye. Doctoral thesis , University of London.

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Abstract

The atypical cadherin and tumour suppressor, Fat, is a molecule with a well-defined role in planar cell polarity. Specifically, it is one of a number of molecules that provides directional cues to cells in the establishment of tissue polarity in a variety of systems and organisms. Less understood is its function as a tumour suppressor. The work presented here is a characterisation of the fat phenotypes, with a view to understanding the mechanisms underlying Fat's ability to restrict proliferation. Using the Drosophila eye as a model system, I have addressed this problem in three ways. First, I examined the patterns of expression of various cell cycle molecules, as well as markers of various stages of the cell cycle. This analysis led me to propose that mutations in fat result in a de-sensitisation of cells to the signalling cascades that are responsible for triggering a transition from proliferation to differentiation in the course of development. As such, I then looked at the ways in which Fat affects the activities of the main signalling pathways involved in Drosophila eye development: Notch, EGFR, Hedgehog, Dpp, and Wingless. From this analysis I found that Fat function can be connected to EGFR, Hedgehog and Wingless signalling. However, I found no evidence to implicate these pathways in Fat-related overgrowth. Finally, I present evidence of parallels between phenotypes of fat and those of components of the Hippo signalling pathway. I show that Fat is required for localisation of Expanded, the most upstream component of this pathway identified to date. I further demonstrate that this localisation is necessary for the function of this pathway and that compromises to this function contribute to Ft-related overgrowth. I also present evidence that suggests this role in growth suppression is independent of Fat's role in dorsal-ventral polarity in the eye.

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