Roles of Cohesins SMC3, RAD21 and STAG3 in Mammalian Meiosis

为什么会有减数分裂特有的粘附素蛋白，不同的粘附素复合体在雄性和雌性减数分裂中扮演什么角色，“无处不在的”粘附素对小细胞有哪些功能？目前，这些问题都不能得到令人满意的回答，但很明显，粘附素在配子发生和减数分裂中扮演着重要的角色。在减数分裂中，粘附素决定染色体的结构，促进突触和重组，是姐妹染色单体凝聚、染色体适当分离和保护端粒完整性所必需的。因此，它们是生殖健康的关键。我们的总体假设是，在男性和女性的减数分裂细胞中，几个特定的粘附素复合体在特定的阶段发挥作用，并发挥特定的功能，但人们对这些功能知之甚少。我们将解决与这一生物学基本问题有关的一些核心问题。基于主要章节概述的关于单个粘附素亚基的特定假设，我们直接的特定目标是：(1)了解粘附素SMC3和RAD21的减数分裂功能和性质(2)确定减数分裂特异粘附素STAG3的蛋白质关联性。在进化上高度保守的SMC3和RAD21是体细胞和减数分裂粘附素复合体的组成部分，像我们最近在减数分裂细胞中观察到的那样，动态和稳定地形成与染色体相关的粘附素池，并且是减数分裂中所有(SMC3)或选择性(RAD21)粘附素复合体的亚单位。然而，尽管有明确的重要和特定的减数分裂功能的迹象，但它们的减数分裂作用并未得到描述，现在将对其进行评估。STAG3是唯一一种减数分裂特异的雄鹿型粘附素，我们假设它在小母细胞中作为粘附素与其他蛋白质相互作用的平台，现在应该对其进行表征。在迄今检测的所有单个减数分裂粘附素缺乏症中，STAG3‘S缺失显示了最戏剧性的染色体表型。我们已经组装了哺乳动物减数分裂粘附素研究领域中可能最全面的一套工具，包括各种复杂的小鼠品系，以解决这些问题。我们希望对我们理解哺乳动物减数分裂中的核心粘附素蛋白做出重大贡献，从而对生殖健康起关键作用，即它们在精母细胞和卵母细胞染色体动力学中的作用及其分子特性。

Why are there meiosis-specific cohesin proteins, which roles do the various cohesin complexes play in male and female meiosis, which functions do “ubiquitous” cohesins contribute to meiocytes? Currently, none of these questions can be satisfactorily answered, and yet it is clear that cohesins play essential roles in gametogenesis, in meiosis. In meiosis, cohesins determine the chromosomal architecture, promote synapsis and recombination, are required for sister chromatid cohesion, proper segregation of chromosomes, and protect telomere integrity. Thus, they are key to reproductive health.Our overall hypothesis is that in male and female meiocytes several specific cohesin complexes act at specific stages and serve specific functions, which are however too little understood. We will address some of the central questions related to this biologically fundamental problem. Based on specific hypotheses concerning the individual cohesin subunits as outlined in the main section, our immediate specific aims are:(1) To understand the meiotic functions and properties of cohesins SMC3 and RAD21(2) To determine protein associations of the meiosis-specific cohesin STAG3The evolutionarily highly conserved SMC3 and RAD21 are components of somatic and meiotic cohesin complexes, form dynamically and stably chromosome-associated cohesin pools as we recently observed in meiocytes, and are either subunit of all (SMC3) or selected (RAD21) cohesin complexes in meiosis. However, despite clear indications for important and specific meiotic functions, their meiotic roles were not described and will now be assessed. STAG3 is the only meiosis-specific STAG-type cohesin, and we hypothesize that in meiocytes it acts as platform for interactions of cohesin with other proteins, which shall now be characterized. STAG3’s deletion shows the most dramatic chromosomal phenotype of all single meiotic cohesin deficiencies tested so far. We have assembled the probably most comprehensive set of tools in the field of mammalian meiotic cohesin research, including a large variety of sophisticated mouse strains, to address these questions. We expect to contribute significantly to our understanding of cohesin proteins central in mammalian meiosis and thus key to reproductive health, i.e. their roles in spermatocyte and oocyte chromosome dynamics and their molecular properties.