The long-term goal of the studies proposed in this application is to define the role of regulated mRNA translation in the control of oocyte cell cycle progression. Meiotic cell cycle progression during vertebrate oocyte maturation is controlled by proteins that are translated from maternally derived mRNAs. In the model system, Xenopus laevis, translational induction of dormant mRNAs encoding cell cycle control proteins must occur in a strict temporal order. Translationally induced maternal mRNAs can be classified based on their temporal activation into early and late class mRNAs following progesterone stimulation. The induction of maternal mRNA translation is directed through regulatory elements in the mRNA 3'untranslated regions that are targeted by sequence-specific RNA binding proteins. We have recently made the seminal finding that the RNA binding protein, Musashi, is the critical temporal determinant of early class mRNA translational induction during Xenopus oocyte maturation. Although Musashi has been implicated in mRNA translational control during neural and epithelial stem cell self renewal, the mechanism by which Musashi regulates mRNA translation is unknown. In the studies proposed in this application, we will test the hypothesis that Musashi-mediated mRNA translational control is a key regulator of cell cycle progression in vertebrate oocytes. Specifically, we will elucidate the mechanisms by which Musashi regulates mRNA translational activation during Xenopus oocyte maturation and determine how Musashi discriminates early class target mRNAs. The experiments described in this proposal will address several key issues regarding the mechanisms of maternal mRNA translational control. We will elucidate the initiating progesterone- dependent regulatory events that impinge on early class mRNA translation. We will determine if Musashi interacts with consensus as well as non-consensus binding sites in the target mRNA 3'UTRs. We will elucidate the relationship of Musashi to the coordination and control of Mos and Ringo mRNA translation and we will test the hypothesis that Musashi-mediated early class mRNA translation is essential for CPE- dependent late class mRNA translation. The insights derived from the study of Musashi function during oocyte maturation will enhance our understanding of this key aspect of reproductive biology.
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