Characterization of a Meiotic Crossover Surveillance System

减数分裂交叉监视系统的表征

基本信息

批准号：
8811987
负责人：
JUDITH L YANOWITZ
金额：
$ 27.24万
依托单位：
MAGEE-WOMEN'S RES INST AND FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8811987
关键词：
Accounting Aneuploidy Biochemical Biological Assay Caenorhabditis elegans Candidate Disease Gene Cell Cycle Cell Nucleus Cell division Chromosome Pairing Chromosome Segregation Chromosome abnormality Chromosomes Communication Congenital Abnormality Core Protein Defect Diploidy Disease Embryo Engineering Ensure Etiology Event Exhibits Exposure to Failure Foundations Generations Genes Genetic Genetic Crossing Over Genetic Recombination Genetic Screening Genetic Variation Germ Cells Grant Haploidy Health Homologous Gene Human Integral Membrane Protein Lead Link Maintenance Meiosis Membrane Proteins Mental Retardation Metaphase Modeling Molecular Genetics Monitor Monosomy Mutagenesis Mutation Nuclear Nuclear Envelope Phenotype Phospho-Specific Antibodies Phosphorylation Ploidies Post-Translational Protein Processing Process Proteins RNA Interference Reporting Research Role Series Signal Transduction Signaling Molecule Spontaneous abortion Structure Synaptonemal Complex System Testing Time Transgenes Trisomy Work base egg gene function genetic information insight irradiation mutant novel offspring premature programs protein complex repaired reproductive segregation sperm cell tool

项目摘要

DESCRIPTION (provided by applicant): The specialized cell division of meiosis results in the formation of haploid gametes from diploid precursors allowing for the maintenance of chromosomal copy number to subsequent generations. Central to this process is the process of crossover recombination that promotes the exchange of genetic information between the maternal and paternal chromosomes. Crossing over both increases offspring diversity and creates a physical link between the homologs that ensures their proper segregation during the first meiotic division. In the absence of crossing over, homologs segregate randomly which can lead to aneuploidy. The importance of establishing a crossover is underscored by multiple checkpoint mechanisms ensure the correct timing and order of the events leading up to crossover formation, specifically pairing, synapsis and double strand break formation. In this grant, we explore a novel surveillance system that is activated by a defect in crossover formation on a single chromosome. This leads to a delay in meiotic progression and loss of the synaptonemal complex between non-recombinant homolog pairs. We use the range of molecular, genetic, biochemical and cytological tools available in C. elegans to define and characterize this surveillance system. The three aims of this grant will dissect out the requirements for communication between the crossover, the meiotic progression machinery, and the synaptonemal complex. We will analyze the requirements for activation of the surveillance system by manipulating crossover number using a system to induce meiotic double strand breaks into spo-11 mutants that cannot form them. We will generate a series of double mutant combinations to define and characterize the cis- and trans-acting signals that promote delay and desynapsis. We propose detailed functional analyses of two downstream targets of the signaling cascade: the integral nuclear membrane protein SUN-1 that is required for chromosome interactions with the nuclear periphery; and SYP proteins, the core components of the synaptonemal complex proteins. Furthermore, we will explore the role of candidate signaling molecules identified in a preliminary RNAi screen. These complementary approaches will provide significant insights into a surveillance system that monitors crossover formation on each chromosome and allows for timely progression through meiosis.

描述（由申请人提供）：减数分裂的专门细胞分裂导致从二倍体前体形成单倍体配子，从而使染色体拷贝数保持到后代。这一过程的核心是跨界重组的过程，该过程促进了母体和父亲染色体之间遗传信息的交换。跨越两者都增加了后代的多样性，并在同源物之间建立了物理联系，从而确保它们在第一个减数分裂划分期间的适当隔离。在没有交叉的情况下，同源物随机分离，这可能导致非整倍性。建立交叉的重要性是由多个检查点机制强调的，可确保正确的时机和顺序导致交叉形成的事件，特别是配对，突触和双链断裂。在这笔赠款中，我们探索了一种新型的监视系统，该系统被单个染色体上的跨界形成中的缺陷激活。这导致减数分裂进程和非重组同源对之间的突触复合物的丧失。我们使用秀丽隐杆线虫中可用的分子，遗传，生化和细胞学工具的范围来定义和表征这种监视系统。这笔赠款的三个目标将剖析交叉，减数分裂进程机制和突发型综合体之间的通信要求。我们将通过使用系统操纵分频器数来诱导减数分裂双链断分解为无法形成它们的SPO-11突变体来分析监视系统激活的要求。我们将生成一系列双重突变体组合，以定义和表征顺式和反式作用信号，这些信号促进延迟和deSynapsis。我们提出了对信号级联的两个下游靶标的详细功能分析：与核外围相互作用所必需的积分核膜蛋白太阳-1；和SYP蛋白，这是突发型复合蛋白的核心成分。此外，我们将探讨在初步RNAi屏幕中鉴定的候选信号分子的作用。这些互补方法将为监视系统提供重要的见解，该系统监视每个染色体上的交叉形成，并通过减数分裂及时进展。