Regulation of chromosome segregation during oocyte meiosis

项目摘要 有性繁殖的有机体利用一种名为减数分裂的特殊细胞分裂程序来减少他们的 染色体数目减半，以产生单倍体配子。此过程的正确执行对于 成功怀孕，因为减数分裂染色体分离错误会导致非整倍体(错误 胚胎中的染色体数目)，这是人类流产和出生缺陷的主要已知原因。 女性的减数分裂特别容易出错，这种脆弱性对人类健康有着深远的影响： 估计有10%-25%的人类胚胎是染色体异常的，而这些缺陷中的绝大多数 源于雌性减数分裂细胞(称为卵母细胞)的问题。然而，尽管女性的重要性 减数分裂对成功繁殖和人类健康来说，令人惊讶的是，人们对其作用机制知之甚少 以确保卵母细胞中准确的染色体分割。 卵母细胞具有一些特殊的特性，这就需要使用新的细胞分裂机制。也许吧 最重要的是，卵母细胞缺乏中心体，中心体在其他类型的细胞中定义和组织纺锤体； 因此，这些细胞中的纺锤体在形态上是不同的。以线虫为模型，我们之前发现 无着丝体卵母细胞纺锤体具有令人惊讶的组织；染色体被微管包裹 沿其两侧运行的束状物，进行侧向接触，而不是形成端接的动粒附着物。 此外，我们还定义了促进这些纺锤体上染色体聚集的新机制，驱动 通过染色体沿这些侧束的运动。因此，我们的工作揭示了一种新的战略 线虫卵母细胞用来控制细胞分裂过程中的染色体动态。 在这些发现的基础上，拟议工作的目标是：1)加深我们对这些发现的理解 独特的机制，以及2)确定调节它们的因素。该系统的一个重要组件是 围绕每对染色体中心形成环状结构的蛋白质复合体(“环复合体”)。 因此，我们的工作将深入研究这种环复合体的功能，以揭示适当的 无着丝体纺锤体组织和染色体动力学。这些方法将使我们能够获得 卵母细胞减数分裂是一种重要但知之甚少的特化细胞 组织。

Project Summary Organisms that reproduce sexually utilize a specialized cell division program called meiosis to reduce their chromosome number by half to generate haploid gametes. Proper execution of this process is crucial for a successful pregnancy, since errors in meiotic chromosome segregation result in aneuploidy (incorrect chromosome number in the embryos), the leading known cause of miscarriages and birth defects in humans. Meiosis in females is especially error prone and this vulnerability has a profound impact on human health: it is estimated that 10-25% of human embryos are chromosomally abnormal, and the vast majority of these defects arise from problems with the female meiotic cells (called oocytes). However, despite the importance of female meiosis for successful reproduction and human health, surprisingly little is known about the mechanisms that act to ensure accurate chromosome partitioning in oocytes. Oocytes have some special features that necessitate the use of novel cell division mechanisms. Perhaps most significantly, oocytes lack centrosomes, which define and organize the spindle poles in other cell types; therefore, spindles in these cells are morphologically distinct. Using C. elegans as a model, we previously found that acentrosomal oocyte spindles have a surprising organization; chromosomes are ensheathed by microtubule bundles that run along their sides, making lateral contacts, instead of forming end-on kinetochore attachments. Moreover, we also defined new mechanisms that facilitate chromosome congression on these spindles, driven by movement of chromosomes along these lateral bundles. Therefore, our work has revealed a new strategy utilized by C. elegans oocytes for controlling chromosome dynamics during cell division. Building on these discoveries, the goals of the proposed work are to: 1) deepen our understanding of these unique mechanisms, and 2) identify factors that regulate them. An important component of this system is a complex of proteins that form a ring structure around the center of each chromosome pair (the “ring complex”). Our work will therefore delve into the functions of this ring complex, to reveal mechanisms essential for proper acentrosomal spindle organization and chromosome dynamics. These approaches will enable us to gain a mechanistic understanding of oocyte meiosis, an important yet poorly understood form of specialized cell division.