Synaptonemal complex assembly and function in meiosis

描述（由申请人提供）：减数分裂是有性生殖所必需的一种特殊细胞分裂过程，分为两个阶段（减数分裂I和减数分裂II），在此过程中，染色体数量减少一半，产生单倍体配子。为了正确分离，染色体必须经历一系列第一次减数分裂所特有的步骤，包括（1）与它们的同源配偶体配对，（2）沿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，导致同源物之间的物理附着（交叉）。重要的是，这些步骤中的任何一个错误都会导致染色体不分离，对胚胎造成灾难性的后果。在人类中，这些事件会导致流产和出生缺陷，如唐氏综合症。我们的重点是调查SC的作用和大分子组装，在减数分裂的中心阶段的结构，其功能知之甚少，尽管其无处不在的存在，从酵母到哺乳动物的许多争论的问题。我们的研究是在线虫C. elegans，一个遗传上顺从的系统，其中丰富的分子和生物化学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）。从这些组件的分析，我们建议解决有关SC的基本问题，包括其组装和拆卸，组成，同源染色体配对，减数分裂重组和染色体分离的作用。我们将通过结合我们在该系统中完整的3-D核结构背景下进行的细胞学观察，遗传和生化方法的结果，以及涉及RNA介导的干扰的强大的全基因组功能基因组学筛选来实现这一点。

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.