Polarity, growth, and morphogenesis of epithelia

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Epithelia are the core cell type of animals, and constitute the most widespread and ancient mode of tissue architecture. Defects in epithelial organization, growth, or morphogenesis underlie a variety of medically devastating disorders, from birth defects to cancer. To understand the biology of humans as well as the rest of the animal kingdom, we need to understand how epithelia take on their distinctive form and how this form enables function. My lab uses a distinctive set of multidisciplinary strategies to investigate these questions in Drosophila, leveraging the deep evolutionary conservation of epithelial biology to uncover general principles applicable across phylogeny. The research described in this MIRA application tackles three fundamental problems of epithelial biology, ranging from the cellular to the tissue and organ scales. First, how are epithelial cells polarized into complementary apical and basolateral domains? Our previous work defined the Scribble module as a basolateral regulator that antagonizes the apical Par complex, but basic questions of the role, relationship, and effector partners of the Scrib proteins remain unanswered, as are the molecular mechanisms that link polarity regulators to the core cellular trafficking machinery. Second, what mechanisms couple growth control in epithelial tissues to cell polarity? We and others have shown that polarity disruption by genetic or physical means activates mitogenic signaling, suggesting that epithelial integrity is an intrinsic control system used to maintain proper size and ensure repair. But how breaches in epithelial homeostasis are detected to trigger proliferation is not understood. Third, how do 3D, multicomponent organs acquire their distinctive shapes? Current paradigms emphasizing cell-autonomous Myosin II contractility derive from analyzing 2D cellular sheets. By studying a simple 3D tube-like organ, we have uncovered multiple novel phenomena including a new morphogenetic movement and an unappreciated mechanism for organ shaping involving extracellular matrix stiffness. Major gaps exist in understanding how cellular and extracellular forces are integrated to drive specific cell behaviors; our expertise uniquely positions us to close these gaps and approach an in toto understanding of organ morphogenesis. The proposed experiments tackle these questions by combining the traditional strengths of Drosophila genetics with new tools with advanced imaging, collaborations with physical scientists, and the development of novel experimental systems. Our results will enhance our understanding of the conserved mechanisms that generate functional epithelial organs during development, and may provide new insights into diseases of epithelial origin.