Mechanisms of acentrosomal spindle assembly and stability during oocyte meiosis

卵母细胞减数分裂过程中心体纺锤体组装和稳定性的机制

• 批准号: 10440938
• 负责人: SARAH Marie WIGNALL
• 金额: $ 34.41万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440938
• 关键词: Acute; Address; Aneuploidy; Area; Biological Assay; Biology; Caenorhabditis elegans; Cell division; Cells; Centrosome; Chromosome Segregation; Chromosome abnormality; Chromosomes; Congenital Abnormality; Coupling; Defect; Dynein ATPase; Embryo; Ensure; Equilibrium; Event; Exhibits; Female; Germ Cells; Goals; Grant; Haploidy; Health; Human; Image; Incidence; Light; Maintenance; Mediating; Meiosis; Microtubule Stabilization; Microtubules; Modeling; Molecular; Mus; Nuclear Envelope; Oocytes; Organism; Pathway interactions; Play; Positioning Attribute; Pregnancy; Process; Proteins; Publishing; Reproduction; Role; Site; Sorting - Cell Movement; Spontaneous abortion; Structure; Testing; Work; cell type; experimental study; insight; novel; programs; protein function; tool

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 must assemble using different mechanisms. Using C. elegans as a model, we previously demonstrated that acentrosomal spindle assembly proceeds by 1) nucleation/stabilization of microtubules adjacent to the disassembling nuclear envelope, 2) sorting of microtubules such that their minus ends are positioned at the periphery of the array, 3) organization of these ends into nascent poles, and 4) coalescence of these sites until bipolarity is achieved. Moreover, we have identified proteins required for key events in this pathway, shedding light on the molecular mechanisms underlying this form of spindle assembly. Building on these discoveries, the goals of the proposed work are to: 1) deepen our understanding of acentrosomal spindle assembly and organization, and 2) investigate mechanisms that promote the formation and stability of acentrosomal spindle poles in both C. elegans and mammalian oocytes. 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 染色体数目减半，产生单倍体配子。正确执行此过程对于 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 由雌性减数分裂细胞（称为卵母细胞）的问题引起。然而，尽管女性很重要 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，人们对其作用机制知之甚少 以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，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必须使用不同的机制来组装。使用秀丽隐杆线虫作为模型，我们 先前证明，中心体纺锤体组装通过以下方式进行：1）成核/稳定化 与可拆卸核膜相邻的微管，2）对微管进行分类，使其负数 末端位于阵列的外围，3) 将这些末端组织成新生极，以及 4) 这些位点的合并直到实现双极性。此外，我们还确定了关键所需的蛋白质 该途径中发生的事件，揭示了这种纺锤体组装形式背后的分子机制。 基于这些发现，拟议工作的目标是：1）加深我们对 中心体纺锤体的组装和组织，2) 研究促进形成的机制 线虫和哺乳动物卵母细胞中的中心体纺锤体极的稳定性。这些方法将 使我们能够获得对卵母细胞减数分裂的机械理解，卵母细胞减数分裂是一种重要但知之甚少的形式 专门的细胞分裂。