Synaptonemal complex assembly and function in meiosis

减数分裂中的联会复合体组装和功能

基本信息

批准号：
6970491
负责人：
Monica P Colaiacovo
金额：
$ 32.21万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2010-07-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：减数分裂是有性生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，通过该过程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特有的步骤，包括（1）与其同源伴侣配对，（2）沿着配对和对齐形成称为联会复合体（SC）的蛋白质结构同源染色体，以及（3）减数分裂重组的完成，导致同源染色体之间的物理附着（交叉）。值得注意的是，这些步骤中的任何一个错误都会导致染色体不分离，给胚胎带来灾难性的后果。对于人类来说，此类事件会导致流产和唐氏综合症等先天缺陷。我们的重点是研究 SC 的作用和大分子组装，SC 是减数分裂过程中处于中心阶段的结构，尽管它从酵母到哺乳动物中普遍存在，但人们对它的功能知之甚少，而且引起了很多争议。我们的研究是在线虫秀丽隐杆线虫中进行的，这是一种遗传上顺从的系统，其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）。从分析这些组件开始，我们建议解决有关 SC 的基本问题，包括其组装和拆卸、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。我们将通过结合在该系统中完整的 3D 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目标。