The role of cell interactions in shaping development

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PROJECT SUMMARY Interactions between cells direct many aspects of embryonic development. The long-term goal of our research program is to learn how cell interactions determine the shape, organization, and function of developing cells, tissues, and organs. Using C. elegans as an in vivo model where genetic analysis, live imaging and cell biology can be combined, we have developed several simple experimental systems to investigate how cell interactions regulate conserved morphogenetic events. The specific goals of this proposal are to use these model systems to fill key gaps in understanding how cells develop polarity, how small tubes form, and how niche cell interactions regulate germ cell biology. In one project, we are investigating how cell contact induces apicobasal polarity. This project addresses two outstanding questions – how cell contacts induce the PAR protein asymmetries that polarize cells, and how PAR proteins elaborate other intracellular asymmetries. We previously discovered that E-cadherin signals to induce polarity by recruiting the RhoGAP PAC-1, which triggers PAR protein asymmetries. We will extend these findings by uncovering new molecular links connecting PAC-1 to the E-cadherin cytoplasmic tail, by identifying additional signaling pathways that contribute to polarization, and by investigating how the PAR protein aPKC induces the formation of epithelial junctions. In a second project, we are investigating how small tubes develop. Small tubes such as capillaries can form in the cytoplasm of a cell when vesicles are targeted to an invading apical domain. It is unclear how vesicles are targeted to this site to form intracellular tubes. We are addressing this question by determining how the excretory cell forms an intracellular tube. We found that PAR proteins localize the exocyst vesicle- tethering complex to direct vesicle fusion events to the invading apical domain, and will extend these findings by investigating how PAR proteins recruit the exocyst and how the initial site for tube formation is specified. In a final project, we are determining how niche cell interactions influence germ cell development. Niche cells wrap membrane extensions around germ cells and stem cells but the significance of these interactions is poorly understood. We discovered that primordial germ cells (PGCs) extend large protrusions that are wrapped and cannibalized by intestinal cells, eliminating most PGC mitochondria. We will determine the importance of PGC lobe cannibalism, testing the hypothesis that it helps ensure the health of germline mitochondria. Together, our findings will reveal new, basic insights into how cell interactions guide critical developmental events, providing a foundation for understanding the contribution of cell interactions in human development and disease.