Homolog pairing in meiosis

减数分裂中的同源配对

基本信息

批准号：
10615149
负责人：
Sean M Burgess
金额：
$ 46.77万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/10615149
关键词：
3-Dimensional Address Aneuploidy Behavior Biochemical Pathway Biology Cell Nucleus Cells Chromosome Pairing Chromosome Structures Chromosome abnormality Chromosomes Congenital Abnormality Data Set Diffusion Drug Prescriptions Ensure Environment Environmental Pollutants 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 Spermatogenesis Spontaneous abortion Synapses Testing Time Waste Products Work Yeasts Zebrafish biophysical properties epigenetic marker homologous recombination insight lens male model organism reproductive response sex telomere time use

项目摘要

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.

项目概要/摘要减数分裂错误导致的染色体异常是出生缺陷和自发性缺陷的主要原因我们的首要目标是了解染色体的组织方式。细胞核有助于同源染色体的正确配对、突触和重组。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。导致同源配对、突触和重组的机制得到了广泛的研究。一系列生物体最终导致了对人类配子非整倍体和不育症的深入了解。模型生物、芽殖酵母和斑马鱼，每种都提供了独特的镜头来解决 3D 染色体的构型受到控制以适应整个核景观的变化我们的工作解决了染色体生物学领域的三个关键问题：1）如何进行减数分裂前期。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不配对的减数分裂 1）为了了解染色体如何移动，我们将检查扩散、受限扩散和主动运动驱动运动对染色体位点的贡献通过使用我们新开发的成像技术比较标记位点随时间变化的 XYZ 坐标数据集来检测酵母我们将把这些结果与基于新开发的染色体行为模型进行比较。我们将测试核孔复合物是否也有助于聚合物的简单生物物理性质。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) 。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在斑马鱼中的工作的基础上，显示配对的初始事件和突触都发生在端粒花束上，这表明较大的细胞核中的配对是可以接受的通过在时间和空间上隔离配对因素，我们将测试端粒是否附着。或者定位在核膜上对于配对很重要，我们将识别表观遗传标记定义染色体的配对特征 3) 了解细胞如何对未配对做出反应。染色体以及这种反应在物种之间，甚至同一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此外，雌性斑马鱼的突触错误是可以容忍的，因此增加了诱人的可能性。反突触染色体检查点的监视和沉默在斑马鱼中不起作用。