Regulation of chromosome segregation during oocyte meiosis

项目摘要 有性繁殖的生物利用一种称为减数分裂的专门细胞分裂程序来减少它们的 染色体数目减半以产生单倍体配子。正确执行这一过程对于 成功怀孕，因为减数分裂染色体分离错误导致非整倍体（不正确 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： 据估计，10-25%的人类胚胎染色体异常，这些缺陷中的绝大多数 由雌性减数分裂细胞（称为卵母细胞）的问题引起。尽管女性的重要性 减数分裂的成功繁殖和人类健康，令人惊讶的是，很少有人知道的机制， 确保卵母细胞中染色体的准确分配。 卵母细胞具有一些特殊的特征，需要使用新的细胞分裂机制。也许 最重要的是，卵母细胞缺乏中心体，在其他细胞类型中，中心体定义和组织纺锤体极; 因此，这些细胞中的纺锤体在形态上是不同的。利用C.作为一个模型，我们以前 发现无中心体卵母细胞纺锤体有一个令人惊讶的组织;染色体被 微管束沿沿着排列，形成横向接触，而不是形成末端着丝粒 附件的权限.此外，我们还定义了促进染色体聚集的新机制， 染色体沿着这些侧束的运动驱动纺锤体上的分离。因此，我们认为， 我们的工作揭示了C.线虫卵母细胞控制染色体动力学 在细胞分裂期间。 基于这些发现，拟议工作的目标是：1）加深我们对 这些新发现的机制和2）阐明它们是如何调节的。一个重要组成部分 这种不依赖于着丝粒的分离系统是一种蛋白质复合物， 每个染色体对的中心（“中间二价环”）。因此，我们的工作将深入到大会， 拆卸，组织和功能，这个环复合体，揭示染色体的基本机制， 在无中心体纺锤体上分离。此外，我们最近也发现， 在这些细胞中存在一种机制;在减数分裂错误的存在下，卵母细胞延迟后期的关键事件 进展，潜在地增加染色体分离的保真度。因此，我们将使用 研究这些细胞中的错误调节并扩展和完善我们的模型的方法组合 染色体的聚集和分离。这些方法将使我们能够获得一个机械的 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.