Characterization of a Meiotic Crossover Surveillance System

项目总结 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 遗传物质在减数分裂过程中被称为交叉重组。超界创造了一种瞬变的， 同系物之间的物理联系，帮助它们在中期对齐，并分离到相反的方向 电线杆。在没有交换的情况下，同源基因随机分离，这可能导致非整倍体，这是一种情况 与出生缺陷和流产有关。交叉队形的重要性通过以下几个方面得到强调 减数分裂事件之间广泛的串扰，确保它们及时有序地完成。我们最近 确定了一种逐条染色体的监测系统，使交叉形成能够及时 减数分裂进程和联会复合体(SC)的稳定，SC是一种稳定的分子支架 同源染色体并列。第一个交叉中间体激活一个系统信号，该信号既 改变其他染色体上SC的动态，使它们变得亚稳定，并促进 染色体的移动，以加强交叉形成。我们鉴定了核膜蛋白SUN-1 而POLO样激酶PLK-2作为这些信号的关键效应器。目前的提案扩大了我们的 监测系统的特征，以提供对这些过程的机械性洞察。遗传 屏幕将用于识别监视系统识别的交叉中间体，以及 信号分子将这一点传递给进程机制和SC。使用以下组合 生化和先进的显微方法，我们将剖析发生在SC上的变化 启动监视系统，以及这如何管理跨界编队。我们还将进一步划定 SUN-1和PLK-2在监测系统中的作用。这些研究将增加我们对 通过监测交叉中间体来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、反复流产、卵巢早衰的病因。 和男性不育，为诊断和治疗干预开辟了道路。

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.