Regulation of the meiotic cell cycle

描述（由申请人提供）：配子发生是有性生殖的核心。它被定义为导致特化生殖细胞形成的发育程序，通常与称为减数分裂的独特细胞分裂有关。配子发生和减数分裂的缺陷对人类健康有着深远的影响。配子发生缺陷导致不育;减数分裂期间染色体错误分离是人类流产和智力迟钝的主要原因。因此，确定配子发生失败和减数分裂染色体错误分离的原因对于理解不孕和残疾（如唐氏综合征）的基本原理至关重要。我们研究的长期目标是确定诱导生殖细胞命运的分子机制，并将经典的有丝分裂细胞周期转化为独特的减数分裂细胞分裂程序。我们以前在芽殖酵母中的研究表明，减数分裂特异性因子作用于典型的细胞周期机制，细胞周期蛋白依赖性激酶（CDK），以实现配子发生和伴随的独特细胞分裂。在这里，我们建议研究这种转变的机械基础。在具体目标1中，我们将确定诱导配子发生的机制。这种细胞命运的转变在所有真核生物中都知之甚少，但这一过程对有性生殖至关重要。我们将 研究芽殖酵母中的生殖细胞命运特化，其中该细胞命运由转录因子Ime 1诱导。先前的工作表明，所有的生殖细胞命运诱导信号收敛于IME 1的启动子。我们将研究如何信号整合发生在IME 1启动子，通过确定在IME 1启动子介导的信号整合的元素，并通过表征控制IME 1表达的调控机制。在具体目标2中，我们将研究将经典的有丝分裂细胞分裂转化为独特的配子发生伴随减数分裂的机制。我们将研究如何不适当的过早表达的CDK亚型，Clb 3-CDK，抑制减数分裂I，而不是诱导有丝分裂。在具体目标3中，我们将研究确保Clb 3-CDKs不过早表达的分子机制。我们以前的研究表明，抑制翻译限制Clb 3的表达减数分裂II。我们现在将确定减数分裂I翻译抑制的分子机制。从酵母到人类，配子发生和减数分裂的机制是高度保守的。因此，与许多其他研究一样，在酵母中发现和表征的调控过程可能会指导高等真核生物包括人类的研究。

DESCRIPTION (provided by applicant): Gametogenesis is central to sexual reproduction. It is defined as the developmental program that leads to the formation of specialized germ cells and is frequently associated with a unique cell division called meiosis. Defects in gametogenesis and meiosis have a profound impact on human health. Defects in gametogenesis lead to infertility; Chromosome mis-segregation during meiosis is the leading cause of miscarriages and mental retardation in humans. Determining the causes of gametogenesis failure and meiotic chromosome mis-segregation is thus vital for understanding the principles underlying infertility and disabilities such as Down's Syndrome. The long-term goal of our studies is to determine the molecular mechanisms that induce the germ cell fate and that transform the canonical mitotic cell cycle into the unique meiotic cell division program. Our previous studies in budding yeast indicate that meiosis-specific factors act on the canonical cell cycle machinery, the cyclin-dependent kinases (CDKs), to bring about gametogenesis and the accompanying unique cell division. Here we propose to study the mechanistic basis of this transformation. In Specific Aim 1 we will determine the mechanisms that induce gametogenesis. This cell fate transition is poorly understood in all eukaryotes yet the process is so critical for sexual reproduction. We will study germ cell fate specification in budding yeast where this cell fate is induced by the transcription factor Ime1. Previous work demonstrated that all germ cell fate-inducing signals converge on the promoter of IME1. We will investigate how signal integration occurs at the IME1 promoter by identifying the elements in the IME1 promoter that mediate signal integration and by characterizing the regulatory mechanisms controlling IME1 expression. In Specific Aim 2 we will examine the mechanisms that transform the canonical mitotic cell division into the unique gametogenesis-accompanying meiotic division. We will investigate how inappropriate premature expression of a CDK subtype, Clb3-CDK, suppresses meiosis I and instead induces a mitotic division. In Specific Aim 3 we will study the molecular mechanisms that ensure that Clb3-CDKs are not expressed prematurely. Our previous studies showed that inhibition of translation restricts Clb3 expression to meiosis II. We will now determine the molecular mechanisms governing meiosis I translational inhibition. The mechanisms governing gametogenesis and meiosis are highly conserved from yeast to human. Thus, as with many other studies, the regulatory processes discovered and characterized in yeast will likely guide the way for studies in higher eukaryotes including human.