Synaptonemal complex assembly and function in meiosis

描述(申请人提供)：减数分裂是有性繁殖所必需的特殊细胞分裂过程，分两个阶段(减数分裂I和减数分裂II)展开，通过这两个阶段染色体数量减少一半，产生单倍体配子。为了正确地分离，染色体必须经历第一次减数分裂所特有的一系列步骤，包括(1)与它们的同源配对，(2)沿着配对和排列的同源染色体形成称为联会复合体(SC)的蛋白质结构，以及(3)完成减数分裂重组，导致同源之间的物理连接(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，给胚胎带来灾难性的后果。在人类中，这类事件会导致流产和唐氏综合症等出生缺陷。我们的重点是研究SC的作用和大分子组装，SC是减数分裂过程中的一个中心阶段的结构，尽管它广泛存在于从酵母到哺乳动物的各个物种中，但其功能却鲜为人知，也是一个有很大争议的问题。我们的研究是在线虫中进行的，这是一个遗传上可服从的系统，在这个系统中，丰富的分子和生化工具可以与强大的细胞学方法相结合。我们最近确定了三个关键的SC组件(SYP-1、SYP-2和SYP-3)。从这些成分的分析开始，我们建议解决与SC有关的基本问题，包括它的组装和拆解、组成以及在同源染色体配对、减数分裂重组和染色体分离中的作用。我们将通过将我们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与遗传和生化方法的结果，以及涉及RNA介导性干扰的强大的全基因组功能基因组学筛选相结合来实现这一点。

DESCRIPTION (provided by applicant): Meiosis is a specialized cell division process essential for sexual reproduction that unfolds in two phases (meiosis I and meiosis II) through which chromosome number is reduced by half generating haploid gametes. To segregate properly, chromosomes must undergo a series of steps that are unique to the first meiotic division, including (1) pairing with their homologous partners, (2) formation of a proteinaceous structure known as the synaptonemal complex (SC) along paired and aligned homologous chromosomes, 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 for the embryo. In humans, such events result in miscarriages and birth defects such as Down syndrome. Our focus is on investigating the roles and the macromolecular assembly of the SC, a structure at center stage during meiosis, whose functions are poorly understood and a matter of much debate despite its ubiquitous presence from yeast to mammals. Our studies are performed in the nematode C. elegans, a genetically amenable system in which abundant molecular and biochemical tools can be coupled with powerful cytological approaches. We have recently identified three critical SC components (SYP-1, SYP-2, and SYP-3). Beginning with the analysis of these components, we propose to address fundamental issues concerning the SC, including its assembly and disassembly, composition, and roles in homologous chromosome pairing, meiotic recombination, and chromosome segregation. We will do this by combining our cytological observations done in the context of an intact 3-D nuclear architecture in this system, with results from genetic and biochemical approaches, and a powerful genome-wide functional genomics screen involving RNA-mediated interference.