Khan, A.; (2008) A screen for interactors of Lkb1 and a role for Lkb1 in the regulation of polarity in the Drosophila eye. Doctoral thesis , University of London.

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Abstract

In humans, loss of function mutations in the Lkb1 serine-threonine kinase are associated with Peutz-Jegher syndrome, an inherited cancer predisposition syndrome. Roles for Lkb1 have been described in various processes, including cell cycle regulation, apoptosis and cell polarity. Comparatively little is understood of the role of Lkb1 in regulating epithelial cell polarity. The establishment and maintenance of apicobasal polarity is a fundamental process that occurs at different stages throughout development. The Lkb1 kinase has been shown to play a conserved role in regulating epithelial cell polarity in C. elegans, Xenopus, Drosophila and mammals. The primary focus of this thesis has been to further characterise the polarity phenotype and mechanisms by which Lkb1 may regulate epithelial polarity in Drosophila. To study the role of Lkb1 in the control of epithelial polarity, I generated loss of function clones in the Drosophila neuroepithelium, the eye. Immunohistochemical and biochemical analysis of Ikh1 clones in the eye reveal that Lkb1 is required for the restriction of apical, junctional and basal determinants to their appropriate domains, for the correct formation of adherens junctions, and for the maintenance of photoreceptor cell morphology. I further demonstrate that in the absence of Lkb1, the beta-catenin homologue Arm and the polarity determinant Par-1 accumulate, and additionally, that Par-1 shows reduced phosphorylation at a site that regulates its localisation and activity. Genetic interactions assays provide further evidence that the pleiotropic effects of Ikhl loss of function may be mediated through the misregulation of Par-1 and Armadillo. I have also conducted a small-scale modifier EMS screen in Drosophila to isolate components of the Lkb1 pathway. We have screened approximately 9,500 flies, and recovered a number of mutants, which can now be mapped and identified using a multi-tiered approach. The role of Lkb1 in regulating cell polarity is conserved from Drosophila to humans. Thus, a deeper understanding of the mechanisms underlying the Lkb1 mediated regulation of epithelial polarity may make a valuable contribution to, and provide a strong basis for progress in the treatment of Peutz-Jegher syndrome.

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