Cell cycle regulation of polarity proteins in proliferating epithelia

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PROJECT SUMMARY Epithelia are polarized layers of adherent cells and the first organized assemblies to emerge during animal development. As they constitute the scaffolds of most organs, they undergo extensive remodeling and proliferation throughout the life of the animal. A long-standing question is how proliferating cells maintain their epithelial organization. Loss of both cell cycle control and epithelial organization result in tissue deformations and epithelial cancers. Loss of cell polarity, in particular, is one of the most prevalent causes of epithelial disorganization. Our central hypothesis is that epithelial polarity is under cell cycle control. Work on proliferative epithelia of the sea anemone Nematostella vectensis has shown that polarity proteins oscillate on and off the apical domain in concert with the cell cycle. Discovery of similar polarity oscillations in various epithelia suggest that cell cycle regulation of epithelial polarity is broadly conserved. However, very little is known about the mechanisms that drive epithelial polarity oscillations and their role in tissue homeostasis. I propose to use the early developing embryos of Nematostella to investigate how the cell cycle regulates epithelial polarity. Nematostella embryos form polarized layers within the first few cleavages and maintain this organization during subsequent synchronous cell divisions. Imaging and molecular biological approaches will allow us to: [1] Dissect whether and how the cell cycle machinery directly modifies apical polarity proteins, and [2] Determine how mitotic changes in cytoskeletal organization control apical protein oscillations. The mechanisms we will uncover are likely to be broadly applicable in other animals and relevant for human epithelia and their associated diseases. .