Regulation of chromosome segregation during oocyte meiosis

卵母细胞减数分裂过程中染色体分离的调控

基本信息

批准号：
10314043
负责人：
SARAH Marie WIGNALL
金额：
$ 29.95万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2023-09-17
项目状态：
已结题

项目摘要

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.

项目概要有性繁殖的生物体利用一种称为减数分裂的特殊细胞分裂程序来减少其染色体数量减半以生成单倍体配子，正确执行此过程对于生成单倍体配子至关重要。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原因。女性减数分裂特别容易出错，这种脆弱性对人类健康产生深远影响：据估计，10-25% 的人类胚胎存在染色体异常，其中绝大多数存在缺陷问题源于雌性减数分裂细胞（称为卵母细胞）的问题，尽管雌性很重要。减数分裂对于成功繁殖和人类健康至关重要，令人惊讶的是，人们对减数分裂的机制知之甚少。采取行动确保卵母细胞中染色体的准确分配。卵母细胞有一些特殊的特征，可能需要使用新的细胞分裂机制。大多数卵母细胞缺乏中心体，而中心体在其他细胞类型中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，我们之前使用秀丽隐杆线虫作为模型。发现中心体卵母细胞纺锤体具有令人惊讶的组织，染色体被包裹着；微管束沿着其侧面延伸，形成横向接触，而不是形成端部着丝粒此外，我们还定义了促进染色体大会和附件的新机制。这些纺锤体上的分离是由染色体沿着这些侧束的运动驱动的。我们的工作揭示了秀丽隐杆线虫卵母细胞用于控制染色体动态的新策略细胞分裂期间。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以及 2) 阐明它们是如何调节的一个重要组成部分。这种独立于着丝粒的分离系统是一种蛋白质复合物，在周围形成环状结构因此，我们的工作将深入研究每对染色体的中心（“中二价环”）。该环复合体的分解、组织和功能，以揭示染色体所必需的机制此外，我们最近还发现了一种调节作用。这些细胞中存在机制；在存在减数分裂错误的情况下，卵母细胞会延迟后期的关键事件因此，我们将使用一个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这些方法将使我们能够获得染色体组装和分离的机制。了解卵母细胞减数分裂，这是一种重要但人们知之甚少的特殊细胞分裂形式。