Watson, AT; (2015) ARID1a is an Inhibitor of Wnt Signalling in Xenopus and Human. Doctoral thesis , UCL (University College London).

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Abstract

Wnt signalling regulates a wide range of events throughout embryonic development, adult homeostasis and the onset of disease. Within the frog Xenopus laevis activation of the Wnt pathway results in one of the first major events during embryogenesis: the establishment of the dorsal-ventral axis. At the molecular level the Wnt pathway in Xenopus embryos is similar to that in many other organisms – including humans – therefore what is learned about protein functions from studies in Xenopus can be extrapolated to other species. My PhD has focussed on the role of ARID1a in the regulation of the Wnt pathway. ARID1a is the largest subunit of the chromatin remodelling BAF complex, which is the vertebrate homologue of the yeast SWI/SNF complex. The BAF complex functions by repositioning nucleosomes within chromatin, and plays a role in a variety of cellular functions such as the regulation of transcription, RNA splicing and DNA damage repair. ARID1a was originally identified in the fruit fly Drosophila, where it was implicated as a repressor of Wg. My studies verify and expand upon this work, investigating the role of ARID1a as a repressor of the Wnt pathway in Xenopus and in Human Embryonic Kidney 293 (HEK293) cells. I carried out a mass spectrometry screen in HEK293 cells and identified two interacting proteins for further study: BCL7a and DDX5. I demonstrate that these two proteins are also able to inhibit Wnt signalling in Xenopus, and suggest mechanisms by which this repression may occur.

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