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 减数分裂对于成功繁殖和人类健康来说，令人惊讶的是，人们对其机制知之甚少 采取行动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有一种令人惊讶的组织；染色体被 沿两侧运行的微管束，进行侧向接触，而不是形成端对上的动粒 附属品。此外，我们还定义了新的机制，促进染色体聚集和 这些纺锤体上的分离，由染色体沿这些侧束的运动驱动。因此， 我们的工作揭示了线虫卵母细胞控制染色体动力学的一种新策略 在细胞分裂过程中。 在这些发现的基础上，拟议工作的目标是：1)加深我们对 这些新发现的机制和2)阐明了它们是如何被监管的。一个重要的组成部分 这种不依赖于动粒的分离系统是一种蛋白质复合体，它在周围形成一个环状结构 每对染色体的中心(“中二价环”)。因此，我们的工作将深入到大会， 这个环复合体的分解、组织和功能，以揭示染色体所必需的机制 无着丝体纺锤体的分离。此外，我们最近还发现，一个监管机构 机制存在于这些细胞中；在存在减数分裂错误的情况下，卵母细胞延迟后期的关键事件 进展，潜在地提高染色体分离的保真度。因此，我们将使用 研究这些细胞中的误差调节并扩展和改进我们的模型的方法的组合 用于染色体聚集和分离。这些方法将使我们能够获得机械性的 了解卵母细胞减数分裂，这是一种重要但知之甚少的特化细胞分裂形式。

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 and segregation 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 newly-discovered mechanisms and 2) to shed light on how they are regulated. An important component of this kinetochore-independent segregation system is a complex of proteins that form a ring structure around the center of each chromosome pair (the “midbivalent ring”). Our work will therefore delve into the assembly, disassembly, organization, and functions of this ring complex, to reveal mechanisms essential for chromosome segregation on acentrosomal spindles. Moreover, we have also recently discovered that a regulatory mechanism exists in these cells; in the presence of meiotic errors, oocytes delay key events in anaphase progression, potentially to increase the fidelity of chromosome segregation. Therefore, we will use a combination of approaches to investigate error regulation in these cells and to expand and refine our models for chromosome congression and segregation. These approaches will enable us to gain a mechanistic understanding of oocyte meiosis, an important yet poorly understood form of specialized cell division.