PROJECT SUMMARY Cell-cell communications among different cell groups, especially between the germline and somatic cells, are key to the development of a functional egg. At the center of germline-soma interactions in the Drosophila model lies the Notch pathway, which plays critical roles in a series of major events during oogenesis. Determining how Notch signaling regulates diverse cellular processes is fundamental to the understanding the regulation of oogenesis. On the other hand, the ovarian model offers an excellent platform to uncover novel regulatory mechanisms of this notoriously important pathway, with roles crucial in development, tissue homeostasis and pathogenesis of a multitude of human diseases. Despite many years of studies, there are still a significant number of unknowns in the field. For example, how Notch regulates growth in different developmental or pathological contexts, how the cell cycle machinery feeds back to modulate the Notch pathway and how environmental stresses impact the signaling output during development and tissue homeostasis. This proposal aims to address these questions using the genetically tractable Drosophila ovarian model system. The proposed studies are based on a series of previous findings and preliminary results. We have shown that Notch signaling induces cell differentiation by switching the follicle cells from the mitotic cycle to an endoreplication cycle, thus restricting cell proliferation. Interestingly, when combined with a loss of cell polarity gene lgl, we found that Notch promotes tissue growth in the follicle cell epithelium. We also found that String (Stg), a Cdc25 homolog, regulates the nuclear access of an active form of Notch, the Notch intracellular domain (NICD). Furthermore, we found that hyperactivation of Notch in follicle cells causes cell death and degeneration of germline cells through phagocytosis. These findings provide us the opportunity to further explore how germline and somatic development are coordinated during normal development and under environmental stresses, and to understand how Notch signaling regulates growth and survival in various biological and pathological conditions. The following three specific aims will be addressed using the ovarian model.1. To determine how Notch regulates tissue growth in different genetic backgrounds. 2. To determine how Cdc25/String regulates NICD nuclear access to impact Notch signaling. And 3. To determine how upregulated Notch activity in follicle cells induces germline cell death. Successful completion of these aims will lead to improved understanding of the diverse effects and regulatory mechanisms of Notch signaling during development and tissue homeostasis. The findings from the proposed studies will help designing new therapeutic strategies for diseases related to aberrant Notch signaling.