TGF-beta regulation of cell proliferation and differentiation in C. elegans

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DESCRIPTION (Provided by Applicant): The coordination between cell proliferation and cell fate specification is fundamental to development and both processes are misregulated in cancer. While many molecular pathways are known that regulate these processes, their interactions in the whole-organism context are poorly understood. The investigator's long-term goal is to understand the developmental and molecular basis for the control of germline proliferation and cell fate specification in C. elegans as a general model for this interaction. The germ cells of most animals, including mammals, proliferate extensively during development. This proliferation is required to produce adequate adult gamete production. Recently, she discovered a role for the TGF-¿ signaling pathway in promoting C. elegans larval germline proliferation. Preliminary data suggest that this role is distinct from the previously characterized role for the same TGF-¿ pathway during the dauer decision, and that the pathway acts germline non-autonomously. The investigator proposes to characterize the cellular mechanisms underlying the defect. In addition, her data reveal a genetic interaction between the highly-conserved TGF-¿ and Notch signaling pathways in this context. Se proposes to test a specific hypothesis regarding their molecular interaction: that TGF-¿ signaling influences Notch ligand expression. Should the data refute her hypothesis, the investigator will take more unbiased approaches to begin to determine the cellular and molecular basis for the effect of TGF-¿ signaling on germline proliferation. These studies will likely provide broadly applicable results and insights into general aspects of cell proliferation control, furthering a basic understanding of development and possibly yielding implications for cancer. PROJECT NARRATIVE: The TGF-¿ and Notch cell signaling pathways are highly conserved in animals and govern many important cellular processes during development, including cell proliferation and cell fate specification. These processes and signaling pathways are implicated in many diseases, especially cancer. The investigator recently discovered a new role for TGF-¿ in germ cell proliferation in C. elegans. She proposes to use this simple model organism to investigate the interaction between TGF-¿ signaling and the Notch pathway as they impinge on germ cell proliferation and differentiation.