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.

项目摘要 重现性利用专门的细胞分裂程序的生物体，称为减数分裂来减少其 染色体数量降到一半以产生单倍配子。正确执行此过程对于 成功怀孕，因为减数分裂染色体分离的错误导致非整倍性（不正确 胚胎中的染色体数），这是人类流产和先天缺陷的已知原因。 女性的减数分裂特别容易出错，这种脆弱性对人类健康产生了深远的影响：它是 估计人类胚胎的10-25％是染色体异常，其中绝大多数这些缺陷 源于女性减数分裂细胞（称为卵母细胞）的问题。但是，尽管女性很重要 减数分裂成功地繁殖和人类健康，令人惊讶的是对行为的机制知之甚少 确保在卵母细胞中进行准确的染色体分配。 卵母细胞具有一些特殊的特征，需要使用新颖的细胞分裂机制。也许 最重要的是，卵母缺乏中心体，该中心体定义和组织其他细胞类型的主轴杆。 因此，这些细胞中的纺锤必须使用不同的机制组装。将秀丽隐杆线虫作为模型，我们 以前证明，艾伦粒纺锤体组装通过1）成核/稳定 微管与拆卸的核包膜相邻，2）微管的排序，使其负 末端位于阵列的外围，3）将这些末端组织成新生的电线杆，4） 这些位点的合并直到达到双极性。此外，我们已经确定了密钥所需的蛋白质 在此途径中的事件，阐明了这种纺锤体组件形式的分子机制。 在这些发现的基础上，拟议的工作的目标是：1）加深我们对 吸头体纺锤体组件和组织，2）研究促进形成的机制 秀丽隐杆线虫和哺乳动物卵母细胞中艾伦粒纺锤体的稳定性。这些方法会 使我们能够获得对卵母细胞减数分裂的机械理解，这是一种重要但知之甚少的形式 专门的细胞分裂。