Homolog pairing in meiosis

项目摘要/摘要 减数分裂错误引起的染色体异常是导致出生缺陷和自发性的主要原因 人类的堕胎。我们的首要目标是了解染色体的组织是如何 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。最基本的 导致同源配对、突触和重组的机制非常保守。对一种广泛的 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洞察。我们用两个 模型生物、萌芽酵母和斑马鱼，每个都提供了一个独特的镜头来解决3D 染色体的构型是为了适应整个核图的变化。 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和主动运动的贡献，2)运动如何促进 染色体之间的分子交易？3)细胞如何感知和响应未配对的减数分裂 染色体以确保生殖的保真度？1)为了了解染色体是如何运动的，我们将研究 扩散、限制扩散和主动运动驱动的运动对染色体基因座的贡献 通过使用我们最新开发的成像技术，比较标记基因座随时间变化的XYZ坐标数据集 输油管道。我们将把这些结果与新开发的染色体行为模型进行比较 聚合物的简单生物物理特性。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)至 了解大得多的脊椎动物细胞核中的染色体组织如何有助于 有效的同源配对我们将建立在我们最近在斑马鱼上所做的工作的基础上，展示配对和 突触都发生在端粒花束上，这表明较大的核中的配对是被调节的。 通过在时间和空间上隔离配对因素。我们将测试端粒附着体 或在核膜上的定位对配对很重要，我们将识别表观遗传标记 定义染色体的配对能力特征。3)了解细胞对未配对的反应 染色体，以及这种反应在物种之间，甚至在相同的性别之间有什么不同 物种，我们将利用我们最近的发现，突触错误导致精子发生停止在 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 对非突触染色体检查点的监视和沉默在斑马鱼中不起作用。

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.