Regulation of the meiotic cell cycle

描述（由申请人提供）：非整倍体是人类流产和智力迟钝的主要原因。因此，确定减数分裂染色体错误分离的原因对于理解唐氏综合症和不孕症的基本原理至关重要。我们研究的长期目标是确定在减数分裂过程中防止染色体错误分离和非整倍体的机制。减数分裂是一个特殊的细胞分裂过程，在此过程中，单个DNA复制阶段之后是两个连续的染色体分离阶段（减数分裂I和减数分裂II）。减数分裂特异性因子作用于与6种Clb细胞周期蛋白（Clb- cdks）相关的细胞周期蛋白依赖性激酶（CDK） Cdc28，产生独特的减数分裂细胞分裂程序。这项拨款有两个目标。我们想要描述Clb-CDKs如何控制减数分裂。(2)我们希望描述减数分裂期间CDKs及其调节因子上发生的变化，并确定导致这些变化的减数分裂特异性调节因子。在Specific Aim 1中，我们将确定在减数分裂II期间阻止Clb1-CDKs活跃的机制，并检查这种调节的重要性。在特异性目标2中，我们将研究如何控制细胞周期蛋白CLB3的翻译。抑制CLB3翻译对减数分裂I染色体分离至关重要。因此，了解CLB3翻译如何被控制以及CLB3如何抑制减数分裂I对于了解减数分裂I染色体分离模式是如何建立的至关重要。在特异性目标3中，我们将确定CLB3如何抑制减数分裂I染色体分离。由于基本的细胞分裂机制从酵母到人类都是高度保守的，并且考虑到本提案中描述的大多数因素也被证明可以控制哺乳动物的减数分裂，因此很可能控制减数分裂的过程也将在物种之间保守。因此，与许多其他细胞周期研究一样，在酵母中发现和表征的调节过程可能会指导包括人类在内的高等真核生物的研究。公共卫生相关性：减数分裂期间产生的非整倍体是人类智力迟钝和流产的主要原因。因此，确定控制减数分裂染色体分离的分子机制和确保配子形成准确发生的监视途径对于理解导致唐氏综合征和不孕症的染色体错误分离的原理至关重要。我们研究的长期目标是在分子水平上确定控制减数分裂染色体分离和配子形成的机制。

DESCRIPTION (provided by applicant): Aneuploidy is the leading cause of miscarriages and mental retardation in humans. Determining the causes of meiotic chromosome mis-segregation is thus vital for understanding the principles underlying Down's Syndrome and infertility. The long- term goal of our studies is to define the mechanisms that prevent chromosome mis-segregation and thus aneuploidy during meiosis. Meiosis is a specialized cell division during which a single DNA replication phase is followed by two consecutive chromosome segregation phases (meiosis I and meiosis II). Meiosis-specific factors act on the cyclin-dependent kinase (CDK) Cdc28 associated with the six Clb cyclins (Clb-CDKs) to bring about the unique meiotic cell division program. This grant has two goals. (1) We want to characterize how Clb-CDKs control meiosis. (2) We want to characterize the changes that occur on CDKs and its regulators during meiosis and to identify the meiosis-specific regulators that cause these changes. In Specific Aim 1 we will determine the mechanisms that prevent Clb1-CDKs from being active during meiosis II and examine the importance of this regulation. In Specific Aim 2 we will investigate how translation of the cyclin CLB3 is controlled. Inhibition of CLB3 translation is essential for meiosis I chromosome segregation. Thus, understanding how CLB3 translation is controlled and how CLB3 inhibits meiosis I is essential to understand how a meiosis I chromosome segregation pattern is established. In Specific Aim 3 we will determine how CLB3 inhibits meiosis I chromosome segregation. Since the basic cell division machinery is highly conserved from yeast to human and given that most of the factors described in this proposal have also been shown to control meiosis in mammals, it is likely that the processes governing meiosis will also be conserved across species. Thus, as with many other cell cycle studies, the regulatory processes discovered and characterized in yeast will likely guide the way for studies in higher eukaryotes including human. Public Health Relevance: Aneuploidy generated during meiosis is the leading cause of mental retardation and miscarriages in humans. Determining the molecular mechanisms governing meiotic chromosome segregation and the surveillance pathways that ensure that gamete formation occurs with accuracy is thus vital for understanding the principles underlying chromosome mis-segregation leading to Down's Syndrome and infertility. The long-term goal of our studies is to define the mechanisms that control meiotic chromosome segregation and gamete formation at the molecular level.