PAR-1, polarity and Wnt signalling in early vertebrate embryos

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There are good reasons to hope that in the future it will be possible to regenerate damaged or diseased parts of the body using the same natural chemicals that generate the structure of the body during normal development of the embryo. For this to be a possibility, it is first essential to get a detailed understanding of how those chemicals, known as morphogens, do their job. This project proposes to analyse a particular morphogen known as Wnt. Wnt is used, among other things, (a) to trigger the switching on of particular genes that make the head and front end of the body and (b) to direct the movements of cells within the embryo so that it is long and narrow (rather than short and round). These two processes happen quite quickly after one another and it is not properly understood how the many cells involved in both processes are able to respond differently to the same Wnt signal. We have been studying another protein, PAR-1, that may help us understand the different Wnt responses. PAR-1 is a protein that exists within cells that makes one end of a cell different from the other. A layer of such cells (known as ?epithelia? e.g. the lining of your gut or kidney) can therefore have one surface be very different from the other (i.e. have epithelial polarity). We believe that Wnt arriving on one surface may act differently from Wnt arriving at the other surface. PAR-1 may be important in this because different versions of the PAR-1 protein react differently to Wnt and may be localised to opposite surfaces of epithelia. To test this, we will (1) check to see if different versions of PAR-1 are indeed localised to the different surfaces, and if so which parts of the structure of PAR-1 enable this differential localisation; (2) determine whether the Wnt-induced cell movements mentioned above, which we know are affected by PAR-1 removal, are affected because the epithelial polarity is disrupted; and (3) find out what PAR-1, which is an enzyme that modifies other proteins, actually does (i.e. which other proteins it modifies), both by testing some candidate proteins and screening for other protein targets. These experiments will help work out the ?wiring diagram? for cell regulation in embryos and ultimately enable cells to be manipulated for therapeutic outcomes.