Mechanisms of epithelial polarity in flies and mammals (360G-Wellcome-207496_Z_17_Z)

Apical-basal polarity is essential for all aspects of epithelial cell function and loss of this polarity is a hallmark of cancer. We have recently found that the endodermal epithelium of the Drosophila adult midgut polarises by a different mechanism from other Drosophila epithelia and may provide a good model for endodermal epithelia in mammals. This proposal aims to understand how polarity is generated in both epithelial types. Firstly, we will examine how the canonical polarity complexes polarise the secretory epithelium of the Drosophila follicle cells. We will investigate how Cdc42 is activated to define the apical domain; we will use optogenetics and super-resolution microscopy to investigate the dynamics and composition of polarity complexes; and we will analyse how cortical polarity organises the microtubule cytoskeleton through the lateral polarity factor, Par-1. Secondly, we will perform clonal screens to identify essential epithelial polarity factors in the Drosophila midgut and characterise their functions. To test whether these factors play conserved roles in mammals, we will knock out their orthologues in mouse intestinal organoids. This research will reveal the fundamental mechanisms that polarise different epithelial types, which is an essential prerequisite for understanding epithelial function and how it is perturbed in diseases like cancer.