Roles of Cohesins SMC3, RAD21 and STAG3 in Mammalian Meiosis

为什么会有减数分裂特异性的内聚蛋白，不同的内聚蛋白复合物在雄性和雌性减数分裂中扮演什么角色，“无处不在”的内聚蛋白对性母细胞有什么功能？目前，这些问题都不能得到满意的回答，但很明显，粘连蛋白在配子发生，减数分裂中发挥着重要作用。在减数分裂中，粘着蛋白决定染色体结构，促进联会和重组，是姐妹染色单体粘着、染色体正确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，在男性和女性的性母细胞中，几个特定的凝聚素复合物在特定的阶段起作用，并发挥特定的功能，但这些功能还知之甚少。我们将讨论与这个生物学基本问题相关的一些核心问题。基于在主要部分中概述的关于单个粘附素亚基的特定假设，我们的直接具体目标是：（1）理解粘附素SMC 3和RAD 21的减数分裂功能和特性（2）确定减数分裂特异性粘附素STAG 3的蛋白质关联。进化上高度保守的SMC 3和RAD 21是体细胞和减数分裂粘附素复合物的组分，如我们最近在减数分裂中观察到的，形成动态和稳定的染色体相关粘附素池，并且是减数分裂中所有（SMC 3）或选择（RAD 21）粘附素复合物的亚基。然而，尽管有明确的迹象，重要的和具体的减数分裂功能，他们的减数分裂作用没有描述，现在将进行评估。STAG3是唯一的减数分裂特异性STAG型粘附素，我们假设，在性母细胞中，它作为平台的粘附素与其他蛋白质的相互作用，这将是现在的特点。STAG3的缺失显示了迄今为止测试的所有单个减数分裂粘附素缺陷中最引人注目的染色体表型。我们已经组装了可能是最全面的一套工具，在哺乳动物减数分裂内聚蛋白的研究领域，包括各种各样的复杂的小鼠品系，以解决这些问题。我们希望能为我们理解哺乳动物减数分裂中的核心凝聚蛋白，从而对生殖健康至关重要，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做出重大贡献。

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.