The overall aim of this proposal is to understand the mechanism that controls entry and exit from the meiotic cell cycle. Understanding the regulation of the germ cell meiotic replication has been instrumental in defining how cells divide. Basic concepts on the cascade of protein phosphorylation that relays a cell through different phases of division, and the checkpoints that monitor completion of critical events and delay progression to the next stage, come largely from studies on meiosis. This knowledge has provided a better understanding of processes involved in development and disease, and has opened a new chapter of pharmacology that targets cell cycle regulators. By investigating the regulation of meiotic progression in mouse oocytes, we have identified novel components essential for meiotic maturation in mammals. Most importantly, we have provided evidence that networks of phosphorylation are as important as protein degradation in the control of entry into metaphase I (MI) and exit from the second metaphase (MII) in mouse oocytes. We now propose to further understand how these pathways are involved in different steps of the cell cycle with experiments organized along the following three Specific Aims. With the first Specific Aim, we will investigate stimulatory and inhibitory phosphorylation of a kinase (Wee1B) which we have shown to be critical at different steps of oocyte meiosis. We will test the hypothesis that the activity of thi enzyme is repressed during MI via phosphorylation at inhibitory sites. The Second Specific aim will be devoted to understanding how kinases/phosphatases generate and maintain networks of phosphorylation during MII arrest and how MII exit is triggered by changes in these networks. With the third Specific Aim, we will investigate how protein stability and translational regulation contribute to assemble and maintain these networks of kinases/phosphatases involved in MII arrest and MII exit. A better understanding of these processes will provide novel insight into the regulation of the meiotic cell cycle and clues on how failure to exit meiosis may lead to aberrant chromosome trafficking, segregation, and compromised embryo development. It will also identify new regulatory networks that can be pharmacologically targeted to manipulate cell replication.

Public Health Relevance

The proposed research is relevant to improving human health and the mission of NIH because it provides a better insight into the mechanisms of development and, therefore, it will improve diganosis and cure of genetic diseases. It will also provide new tools to manipulate the biochemical machineries essential to direct cell replication and differentiation for tissue regeneration.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Melillo, Amanda A
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University of California San Francisco
Obstetrics & Gynecology
Schools of Medicine
San Francisco
United States
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