Synaptonemal Complex Assembly and Function in Meiosis

描述(申请人提供)：减数分裂是一种特殊的细胞分裂过程，导致单倍体配子(即卵子和精子)的形成，因此对有性繁殖和产生遗传多样性是必不可少的。染色体减半是在单轮DNA复制和连续两轮染色体分离(减数分裂I和减数分裂II)之后完成的。获得准确的染色体分离对于单倍体配子的成功形成至关重要。为了正确地分离，染色体必须经历减数分裂I特有的一系列步骤，包括：(1)同源配对，(2)在排列的同源物之间形成“拉链状”结构(联会复合体或SC)，(3)减数分裂重组完成，导致同源物之间的物理连接(交叉)。值得注意的是，这些步骤中的任何一个步骤中的错误都会导致染色体不分离，导致灾难性的后果，包括流产和唐氏综合症等出生缺陷。我们的目标是研究SC的作用、大分子组装和调控，尽管SC从酵母到人类无处不在，但其功能尚不清楚，也是一个有很大争议的问题。关注这一目标将揭示突触如何与减数分裂进程的调节相交，并促进准确的染色体分离。我们正在通过研究线虫线虫来解决这个重要问题，线虫线虫是减数分裂研究的理想模式系统，适用于各种遗传、分子、生化和细胞学方法。我们最近鉴定了四个关键的SC组分(SYP-1、SYP-2、SYP-3和SYP-4)，它们是调控SC组装(CRA-1)、减数分裂重组(HIM-18)、以及减数分裂I中SC拆解和姐妹染色单体聚集的蛋白(LAB-1)。从分析这些蛋白质在减数分裂过程中发挥作用的分子机制开始，我们建议解决配对、突触和重组如何相交和调控的基本问题，从而实现准确的染色体分离。我们将结合在这个系统中完整的3-D核结构的背景下所做的细胞学观察，以及来自分子、遗传和生化方法的结果来实现这一点。综上所述，这一应用将为准确的减数分裂染色体分离的分子机制提供重要的新见解，并推动我们对高等真核生物中类似过程的理解。 公共卫生相关性：减数分裂是一种专门的细胞分裂程序，需要产生卵子和精子，因此对人类生殖至关重要。据预测，减数分裂过程中的错误约占人类所有流产和出生缺陷(如唐氏综合症)的35%。这项研究将探讨促进减数分裂染色体准确分离的分子机制，从而为开发有效的预防策略奠定基础。

DESCRIPTION (provided by applicant): Meiosis is a specialized cell division process that results in the formation of haploid gametes (i.e.: eggs and sperm) and is therefore essential for sexual reproduction and generating genetic diversity. The reduction of the chromosome complement by half is accomplished by following a single round of DNA replication with two consecutive rounds of chromosome segregation (meiosis I and meiosis II). Achieving accurate chromosome segregation is paramount for the successful formation of haploid gametes. To segregate properly, chromosomes must undergo a series of steps that are unique to meiosis I, including: (1) homologous pairing, (2) formation of a "zipper-like" structure (the synaptonemal complex or SC) between aligned homologs, and (3) completion of meiotic recombination leading to physical attachments (chiasmata) between homologs. Significantly, errors in any of these steps lead to chromosome nondisjunction, with disastrous consequences including miscarriages and birth defects such as Down syndrome. Our goal is to investigate the roles, macromolecular assembly and regulation of the SC, whose functions are poorly understood and a matter of much debate despite its ubiquitous presence from yeast to humans. Focusing on this goal will reveal how synapsis intersects with the regulation of meiotic progression and promotes accurate chromosome segregation. We are addressing this important issue by studying it in the nematode C. elegans, an ideal model system for meiotic studies, amenable to various genetic, molecular, biochemical and cytological approaches. We have recently identified four critical SC components (SYP-1, SYP-2, SYP-3 and SYP-4), proteins that regulate SC assembly (CRA-1), meiotic recombination (HIM-18), and SC disassembly and sister chromatid cohesion during meiosis I (LAB-1). Beginning with the analysis of the molecular mechanisms through which several of these proteins function during meiosis, we propose to address the fundamental issues of how pairing, synapsis and recombination intersect and are regulated resulting in accurate chromosome segregation. We will do this by combining cytological observations done in the context of an intact 3-D nuclear architecture in this system, with results from molecular, genetic and biochemical approaches. Taken together, this application will provide significant new insights into the molecular mechanisms underlying accurate meiotic chromosome segregation and move us forward in our understanding of analogous processes in higher eukaryotes. PUBLIC HEALTH RELEVANCE: Meiosis is a specialized cell division program required for the production of eggs and sperm and therefore essential for human reproduction. Errors during meiosis are predicted to account for approximately 35% of all miscarriages in humans and birth defects such as Down syndrome. The proposed research will investigate the molecular mechanisms promoting accurate meiotic chromosome segregation thereby laying the foundation for the development of effective preventive strategies.