Homolog pairing in meiosis

减数分裂中的同源配对

• 批准号: 10406081
• 负责人: Sean M Burgess
• 金额: $ 46.7万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406081
• 关键词: 3-Dimensional; Address; Aneuploidy; Animal Model; Behavior; Biochemical Pathway; Biology; Cell Nucleus; Cells; Chromosome Pairing; Chromosome Structures; Chromosome abnormality; Chromosomes; Congenital Abnormality; Data Set; Diffuse; Diffusion; Drug Prescriptions; Ensure; Environment; Environmental Pollution; Equilibrium; Event; Exposure to; Female; Food Container; Gametogenesis; Genetic; Genetic Recombination; Germ Cells; Goals; Homologous Gene; Human; Image; Infertility; Lead; Meiosis; Meiotic Prophase I; Modeling; Molecular; Motion; Motor; Movement; Nuclear; Nuclear Envelope; Nuclear Pore Complex; Organism; Outcome; Pathway interactions; Polymers; Positioning Attribute; Pregnancy loss; Process; Prophase; Reproductive Health; Role; Saccharomycetales; Same-sex; Spermatogenesis; Spontaneous abortion; Synapses; Testing; Time; Transact; Waste Products; Work; Yeasts; Zebrafish; base; biophysical properties; epigenetic marker; homologous recombination; insight; lens; male; reproductive; response; telomere; time use

Project Summary/Abstract Chromosome abnormalities due to meiotic errors are a leading cause of birth defects and spontaneous abortions in humans. Our overarching goal is to understand how the organization of chromosomes in the nucleus contributes to the correct pairing, synapsis, and recombination of homologous chromosomes during meiosis I prophase– and how infidelity in these processes lead to chromosomal abnormalities. The basic mechanisms leading to homolog pairing, synapsis and recombination are well conserved. The study of a wide range of organisms has ultimately led to insights into human gamete aneuploidy and infertility. We use two model organisms, budding yeast and zebrafish, each providing a unique lens to address how the 3D configuration of chromosomes is governed to accommodate the changes in the nuclear landscape throughout meiotic prophase. Our work addresses three key questions in the field of chromosome biology: 1) How do chromosomes balance the contributions of diffusive versus active motion, 2) How does movement promote molecular transactions between chromosomes? And 3) how do cells sense and respond to unpaired meiotic chromosomes to ensure reproductive fidelity? 1) To understand how chromosomes move, we will examine the contributions of diffusion, constrained diffusion, and active motor-driven movement on chromosomal loci in yeast by comparing data sets of XYZ coordinates of tagged loci over time using our newly developed imaging pipeline. We will compare these outcomes with newly developed models of chromosome behavior based on simple biophysical properties of polymers. We will test if the nuclear pore complex also contributes to chromosome motion, building on our discovery of a role of the NPC in meiotic chromosome dynamics. 2) To understand how the organization of chromosomes in the much larger vertebrate nucleus contributes to effective homolog pairing we will build on our recent work in zebrafish showing the initial events of pairing and synapsis all take place at the telomere bouquet, suggesting that pairing in the larger nucleus is accommodated by temporally and spatially sequestering pairing factors in time and space. We will test if telomere attachment or positioning at the nuclear membrane is important for pairing, and we will identify the epigenetic markers that define pairing-competent features of chromosomes. 3) To understand how cells respond to unpaired chromosomes and how does this response differ between species, and even between sexes of the same species, we will take advantage of our recent findings that synaptic errors cause arrest in spermatogenesis in zebrafish males. Furthermore, synaptic errors in females are tolerated, thus raising the tantalizing possibility that the surveillance and silencing of asynapsed chromosomes checkpoints does not operate in zebrafish.

项目总结/摘要 由于减数分裂错误导致的染色体异常是出生缺陷和自发性染色体异常的主要原因。 人类的堕胎我们的首要目标是了解染色体的组织在 细胞核有助于同源染色体的正确配对、联会和重组， 减数分裂I前期-以及这些过程中的不忠如何导致染色体异常。基本 导致同源物配对、突触和重组的机制是非常保守的。研究一个广泛的 一系列生物体的研究最终使人们对人类配子非整倍性和不育性有了更深入的了解。我们使用两 模型生物，芽殖酵母和斑马鱼，每个都提供了一个独特的透镜来解决3D 染色体的构型是受控制的，以适应整个过程中细胞核景观的变化。 减数分裂前期我们的工作解决了染色体生物学领域的三个关键问题：1）如何 染色体平衡扩散运动与主动运动的贡献，2）运动如何促进 染色体之间的分子交换3）细胞如何感知和响应未配对的减数分裂 确保生殖忠诚的染色体1)为了了解染色体是如何移动的，我们将检查 扩散、约束扩散和主动电机驱动运动对染色体位点的贡献 酵母通过比较数据集的XYZ坐标的标记基因座随着时间的推移，使用我们新开发的成像 渠道.我们将比较这些结果与新开发的染色体行为模型的基础上， 聚合物的简单生物物理性质。我们将测试核孔复合体是否也有助于 染色体运动，建立在我们发现NPC在减数分裂染色体动力学中的作用的基础上。2)到 了解更大的脊椎动物细胞核中染色体的组织如何有助于 有效的同源配对，我们将建立在我们最近的工作，在斑马鱼显示的初始事件配对， 突触都发生在端粒束，这表明较大的细胞核中的配对是适应的 通过在时间和空间上隔离时间和空间上的配对因素。我们将测试端粒附着 或定位在核膜上对配对很重要，我们将确定表观遗传标记， 定义染色体的配对能力特征。3)为了了解细胞如何对未配对的 染色体以及这种反应在物种之间，甚至在同一物种的性别之间有何不同？ 物种，我们将利用我们最近的发现，即突触错误导致精子发生停滞， 雄性斑马鱼此外，女性的突触错误是可以容忍的，因此增加了诱人的可能性， 不联会染色体检查点的监视和沉默在斑马鱼中不起作用。