Developmental Control of the Cell Cycle in Male Meiosis

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DESCRIPTION (provided by applicant): Developmental programs must impose cell type specific controls on cell cycle progression for normal embryonic development, cell differentiation, tissue renewal and repair, and prevention of cancer. A striking case of developmental^ regulated cell cycle control is the meiotic cell cycle essential for all sexual reproduction. Meiosis features an extended G2 phase, meiotic prophase, during which many genes required for gamete differentiation are transcribed. The duration of meiotic prophase is controlled differently in males than in females. We are investigating the mechanisms that regulate timing of the G2/M transition of meiosis I in males in Drosophila as a model system. We found that developmental^ programmed translational control regulates timing of the G2/M transition of male meiosis I and coordinates meiotic cell cycle progression with the transcription program for spermatid differentiation by two independent pathways. Translational repression delays expression of cyclin B protein, and translational controls link expression of boule protein to the transcriptional program for spermatid differentiation. In turn, boule (a homolog of human BOULE and D/\Z), regulates translation of the cell cycle phosphatase cdc25/twine. We will investigate the molecular mechanisms of how Boule acts to relieve translational repression of cdc25/twine and how translational repression of Cyclin B is relieved in mature spermatocytes, dependant on elF4G2, a novel homolog of the translational initiation machinery component elF4G. We will investigate the mechanisms that delay translation of cyclin B protein in immature spermatocytes, including the mode of action of the RNA binding protein Tsr. To discover the regulatory mechanisms that make meiotic cell cycle progression depend on successful expression of spermatid differentiation genes in primary spermatocytes, we will identify c/s^ acting sequences responsible for translational repression of boule in tTAF mutant spermatocytes, screen for possible translational regulators that bind, and test their role in vivo. To discover how translation of boule is derepressed in response to tTAF function, we will identify candidate translational activators expressed under tTAF control, and determine whether heterologous expression allows boule translation in tTAF mutant spermatocytes. Our findings will illuminate the mode of action and regulation of the conserved RNA binding protein Boule and suggest mechanisms to test for similar function during mammalian spermatogenesis.