The Roles of Cohesin Regulator Proteins in Mammalian Meiosis

粘附素是姐妹染色单体凝聚所必需的，在DNA重组和修复、基因表达调控、端粒保护以及可能的其他过程中起着至关重要的作用。为了将粘附素装载到染色体上，维持其与染色体的联系，并建立和溶解姐妹染色单体凝聚力，有丝分裂过程中需要几个正反凝聚因子(PRO：ESCO1，ESCO2，Sororin；主要抗：HDAC8，WAPL，Pds5A，Pds5B)。所有这些粘附素调节因子在哺乳动物减数分裂中的作用几乎完全未知。目前尚不清楚，在进入减数分裂时，粘附素是如何加载的，以及凝聚力是如何建立、维持和准备在减数分裂后期释放的。这种知识的缺乏是非常令人不满意的，因为粘附素是减数分裂凝聚力、减数分裂染色体轴环结构、同源染色体配对(突触)、同源染色体之间的重组、保护减数分裂染色体端粒以及两次减数分裂中染色体分离的核心。如果这些过程中的任何一个失败，配子发生要么被取消，要么异常进行，往往会给后代带来严重的后果，如非整倍体。因此，与减数分裂染色体相关的粘附素必须受到严格的调控。我们的长期目标是了解这些关键的控制措施。基于我们的初步数据清楚地表明了减数分裂的功能，我们建议首先研究三种粘附素调节因子，ESCO2，HDAC8和Pds5B，它们现在可以进行遗传和生化研究。产生了具有可诱导缺陷的小鼠品系，并将使用各种方法和途径进行分析。考虑到我们最近根据粘附素恶化假说(Jessberger，2010,2012)证明了粘附素在避免年龄依赖性卵母细胞非整倍体中的关键作用(Lister等人，2010；Revenkova等人，2010)，我们预计拟议的研究不仅对于理解哺乳动物的配子发生和减数分裂，而且对人类健康都具有核心重要性。

Cohesin is essential for sister chromatid cohesion and critically involved in DNA recombination and repair, regulation of gene expression, telomere protection and possibly other processes. To load cohesin onto chromosomes, to maintain its association with chromosomes, and to establish and dissolve sister chromatid cohesion, several pro- and anti-cohesion factors are required in mitosis (pro: ESCO1, ESCO2, Sororin; mostly anti: HDAC8, WAPL, PDS5A, PDS5B). Roles in mammalian meiosis are almost entirely unknown for all of these cohesin regulating factors. It is unclear, how cohesins are loaded upon entry into meiosis and how cohesion is established, maintained and prepared for release later during meiosis. This lack of knowledge is very unsatisfying, since cohesin is central to meiotic cohesion, meiotic chromosome axes-loop architecture, pairing of homologous chromosomes (synapsis), recombination between homologous chromosomes, protection of telomeres of meiotic chromosomes, and chromosome segregation in both meiotic divisions. If any of these processes fails, gametogenesis is either abrogated or proceeds aberrantly with often severe consequences for the offspring such as aneuploidy. Thus, cohesins association with meiotic chromosomes must be tightly regulated. Our long-term aim is to understand these crucial controls. Based on our preliminary data clearly suggesting functions in meiosis, we propose to begin by studying three of the cohesin regulatory factors, ESCO2, HDAC8, and PDS5B, which became now amenable to genetic and biochemical studies. Mouse strains with inducible deficiencies were generated and are to be analyzed using a variety of methods and approaches. Considering our recent demonstration of the key role of cohesin in avoiding age-dependent oocyte aneuploidy (Lister et al., 2010; Revenkova et al., 2010) according to the cohesin deterioration hypothesis (Jessberger, 2010, 2012), we expect the proposed studies to be of central importance not only for understanding mammalian gametogenesis and meiosis, but also for human health.