Developmental regulation of the cell cycle machinery

PROJECT SUMMARY The development of an organism requires a delicate balance of cell proliferation with cell cycle exit events that necessitates the regulation of the cell cycle machinery to interface with the developmental program. Among critical cell cycle exit events during development are cell differentiation and cell cycle pause, also known as quiescence. The decision to proliferate or exit the cell cycle is influenced by a multitude of factors, including developmental, environmental and nutritional cues. Failures in these decisions are the cause of cancer, as well as developmental abnormalities and aging-related disorders. My overarching goal is to address how the core cell cycle machinery integrates diverse inputs to execute the decision to enter and exit the quiescent state and to couple the cell cycle to cell fate determination during development. My prior work employing C. elegans provided fundamental new insights into the control of cell cycle state transitions in an in vivo context. Using the developing germline, a tissue of utmost importance for the accurate propagation of the genomic information across generations and where cell cycle regulation is tied to nutrient signaling, I uncovered a conserved molecular mechanism that allows for the accumulation of cyclin B to drive entry into mitosis. I also determined how the cell cycle machinery is specialized in different developmental contexts to promote cell proliferation, with particular emphasis on the Cdk1-Cyclin B complex that coordinates mitotic entry and exit events. In this proposal, my group will capitalize on our expertise in cell cycle regulation mechanisms, in vitro biochemistry and developmental analyses to delineate the molecular mechanism by which germline precursors enter into and exit from a non-cannonical form of quiescence at the G2 stage of the cell cycle in response to nutrient signaling, to address how these signals interface with the pathways that regulate entry into mitosis, and to determine how the cell cycle machinery intersects with cell fate specification to promote cell differentiation during embryonic development. This work will drive new understanding of how cell cycle decision points are regulated during development, which could help prevent and/or treat disorders originating from cell proliferation defects.