Developmental Control of the Cell Cycle in Male Meiosis

描述（由申请人提供）：发育计划必须对细胞周期进程进行细胞类型特异性控制，以实现正常胚胎发育、细胞分化、组织更新和修复以及癌症预防。发育调节细胞周期控制的一个突出例子是减数分裂细胞周期，这是所有有性生殖所必需的。减数分裂的特征是延长的G2期，减数分裂前期，在此期间，配子分化所需的许多基因被转录。减数分裂前期的持续时间在男性和女性中的控制不同。我们正在调查的机制，调节减数分裂的G2/M转换的时间在果蝇作为一个模型系统的男性。我们发现，发育程序化翻译控制调节男性减数分裂I的G2/M转换的时间，并通过两条独立的途径协调减数分裂细胞周期进程和精子细胞分化的转录程序。翻译抑制延迟了细胞周期蛋白B蛋白的表达，翻译控制将boule蛋白的表达与精子细胞分化的转录程序联系起来。反过来，boule（人类BOULE和D/Z的同源物）调节细胞周期磷酸酶cdc 25/cdc 25的翻译。我们将研究Boule如何发挥作用，以缓解cdc 25/cdc的翻译抑制和如何在成熟精母细胞中缓解细胞周期蛋白B的翻译抑制的分子机制，依赖于elF 4 G 2，一种新的同源物的翻译起始机制组成部分elF 4 G。我们将研究延迟未成熟精母细胞中细胞周期蛋白B蛋白翻译的机制，包括RNA结合蛋白Tsr的作用模式。为了发现减数分裂细胞周期进程依赖于初级精母细胞中精子细胞分化基因的成功表达的调控机制，我们将鉴定负责tTAF突变精母细胞中boule翻译抑制的c/s^作用序列，筛选可能结合的翻译调控因子，并测试它们在体内的作用。要发现如何翻译的boule是derepressed响应tTAF功能，我们将确定候选翻译激活剂tTAF控制下表达，并确定是否异源表达允许boule翻译tTAF突变精母细胞。我们的研究结果将阐明保守的RNA结合蛋白Boule的作用和调节模式，并提出在哺乳动物精子发生过程中测试类似功能的机制。

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.