How do cells organize themselves internally, in order to take on a specific external form and function? Each of the >200 cell types in the human body has a distinct, sometimes radical architecture, as exemplified by the elaborate morphologies and numerous membrane domains of neurons. Yet how these properties arise from the relatively isotropic newborn cell remains largely unknown. While the basic elements underlying cell architecture —the cytoskeleton and protein trafficking system— have been identified, the ways in which these systems are organized to dictate particular cell shapes and polarities remain mysterious. We are exploring the biology of cell architecture by studying a simple cell type —epithelia— in a highly manipulable model organism --Drosophila.
Epithelia are the core cell type of animal tissues and, with their highly regular morphology, represent an ideal system in which to uncover general principles of cell architecture. The polarization of the plasma membrane and cytocortex into distinct apical and basolateral compartments offers a dramatic instance of regulated organization, while the distinctive shapes of squamous, cuboidal and columnar epithelia exemplify how this organization can be regulated to achieve specific structures. Because these aspects of epithelial organization are closely conserved across animal species, our findings on flies are likely to be directly relevant to vertebrates as well. Our general goal is to gain a global picture of the molecules and mechanisms that mediate epithelial organization.
In addition to these cell biological questions, the laboratory also studies how epithelial architecture contributes to organismal development. We particularly seek to understand how epithelial organization promotes the control of cell proliferation, a surprising connection revealed by the Drosophila 'neoplastic' tumor suppressor genes (TSGs), which simultaneously control both cell polarity and tissue growth. Loss of any neoplastic TSG induces uncontrolled growth of disorganized cells that show several striking similarities to malignant human tumors; we seek to uncover the mechanism involved. In another line of research, we study how dynamic changes in cellular properties such as polarity and adhesion are regulated and interface with physical forces during epithelial morphogenesis.
Our research strategy emphasizes the importance of studying epithelial tissues in vivo. Much of animal biology happens in the context of epithelial sheets, and studies in this context allow exploration of critical biological phenomena that cannot be replicated in isolated situations. Our strategy also recognizes the value of unbiased forward genetic screens as entry points to understanding biological problems. This discovery-based approach opens up new areas and inspires conceptual advances as a prerequisite to mechanistic studies. We therefore combine genetic, cell biological, biochemical, and imaging approaches to take a broad-based, function-centered approach to epithelial biology