Moore, RE; (2013) Control of microtubule dynamics by Par3 is required for contact inhibition of locomotion. Doctoral thesis , UCL (University College London).

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Abstract

Cell-cell adhesion junctions are essential for the maintenance of epithelial cell polarity and thus tissue integrity. However, the role of such proteins in collectively migrating mesenchymal cells has not yet been investigated. Here, I investigate the role of the polarity protein Par3 in the neural crest, a collectively migrating embryonic cell population. Par3 is localised to the adhesion complex and is important in the definition of apico-basal polarity in epithelial cells, but the localisation and function of Par3 in mesenchymal cells is not well characterised. Here, I show that Par3 is localised to the cell-cell contact in neural crest cells and is important for contact inhibition of locomotion, a phenomenon essential for appropriate migration of neural crest cells. Par3 promotes contact inhibition of locomotion by controlling microtubule dynamics at the site of cell-cell contact. A morpholino designed to inhibit Par3 reduces microtubule depolymerisation at the site of cell-cell contact and abrogates contact inhibition of locomotion. This can be rescued by a low concentration of the microtubule depolymerising drug nocodazole, by inhibiting Rac1, or by coinjection with a morpholino against the Rac1-GEF Trio. Further, Trio and Par3 interact, as shown by co-imunoprecipitation, and localise at the cell contact, as shown by immunofluorescence. I propose that Par3 sequesters Trio and prevents Rac1 activation at cell contacts, thus inhibiting Rac1 promotion of microtubule stability.

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