Characterization of a Meiotic Crossover Surveillance System

项目摘要 在卵子和精子的形成过程中，母系和父系遗传的染色体交换 遗传物质的过程称为减数分裂交叉重组。穿越产生了一个瞬变， 同源物之间的物理联系，帮助它们在中期对齐并分离到相反的 波兰人如果没有交换，同源物会随机分离，这会导致非整倍体， 与出生缺陷和流产有关。交叉形成的重要性是由强调 在减数分裂事件之间的广泛的串话，确保它们及时有序的完成。我们最近 确定了一个染色体的染色体监测系统，夫妇交叉形成及时 减数分裂进程和联会复合体（SC）的稳定，联会复合体是稳定 并置同源染色体。第一个交叉中间体激活一个系统信号， 改变SC在其他染色体上的动力学，使它们亚稳定， 染色体迁移率，以加强交叉形成。我们鉴定了核膜蛋白SUN-1 以及polo样激酶PLK-2作为这些信号的关键效应物。目前的建议扩大了我们的 监测系统的表征，以提供对这些过程的机械见解。遗传 筛选将用于识别由监督系统识别的交叉中间体， 信号分子将其传递给进展机制和SC。 生物化学和先进的显微镜方法，我们将解剖出发生在SC的变化， 监控系统的激活以及它如何调节交叉形成。我们还将进一步描述 SUN-1和PLK-2在监视系统中的作用。这些研究将增加我们对 通过监测交叉中间体促进基因组稳定性的细胞机制。这些 研究可以深入了解出生缺陷、复发性流产、卵巢早衰、 和男性不育症，开辟了诊断和治疗干预的途径。

PROJECT SUMMARY During the formation of egg and sperm, the maternally- and paternally-inherited chromosomes exchange genetic material in the process known as meiotic crossover recombination. Crossing over creates a transient, physical connection between the homologs that helps them align at metaphase and segregate to opposite poles. Without crossing over, homologs segregate randomly which can lead to aneuploidy, a condition associated with birth defects and miscarriage. The importance of crossover formation is underscored by the extensive crosstalk between meiotic events that ensures their timely and orderly completion. We recently identified a chromosome-by-chromosome surveillance system that couples crossover formation to timely meiotic progression and to stabilization of the synaptonemal complex (SC), a molecular scaffold that stably juxtaposes homologous chromosomes. The first crossover intermediate activates a systemic signal that both changes the dynamics of the SC on the other chromosomes, making them meta-stable, and also promotes chromosome mobility to potentiate crossover formation. We identified the nuclear membrane protein SUN-1 and the polo-like kinase, PLK-2, as key effectors of these signals. The current proposal expands our characterization of the surveillance system to provide mechanistic insight into these processes. Genetic screens will be used to identify the crossover intermediates that are recognized by the surveillance system and the signaling molecules that communicate this to the progression machinery and SC. Using a combination of biochemical and advanced microscopic approaches, we will dissect out the changes that occur to the SC upon activation of the surveillance system and how this regulates crossover formation. We will also further delineate the roles of SUN-1 and PLK-2 in the surveillance system. These studies will increase our understanding of cellular mechanisms that promote genome stability through the monitoring of crossover intermediates. These studies can provide insight into the etiology of birth defects, recurrent miscarriage, premature ovarian failure and male infertility, opening avenues for diagnosis and therapeutic intervention.