Characterization of a Meiotic Crossover Surveillance System

减数分裂交叉监视系统的表征

• 批准号: 8847475
• 负责人: JUDITH L YANOWITZ
• 金额: $ 1.74万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847475
• 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; insight; irradiation; mutant; novel; offspring; premature; programs; protein complex; repaired; reproductive; segregation; sperm cell; tool

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(申请人提供)：减数分裂的特殊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续世代。这一过程的核心是交叉重组过程，该过程促进了母本和父本染色体之间的遗传信息交换。两者杂交增加了后代的多样性，并在同源物之间建立了物理联系，以确保它们在第一次减数分裂期间得到适当的分离。在没有交换的情况下，同源基因随机分离，这可能导致非整倍体。多个检查点机制确保导致交叉形成的事件的正确时间和顺序，特别是配对、突触和双链断裂形成，突显了建立交叉的重要性。在这项资助中，我们探索了一种新的监测系统，该系统由单个染色体上的交叉形成缺陷激活。这导致减数分裂进程的延迟和非重组同源对之间联会复合体的丢失。我们使用线虫可用的一系列分子、遗传、生化和细胞学工具来定义和描述这个监测系统。这项拨款的三个目标将剖析交叉、减数分裂进程机制和联会复合体之间的通信要求。我们将通过操纵交叉数来分析激活监视系统的要求，使用一个系统将减数分裂双链断裂诱导到无法形成双链断裂的SPO-11突变体中。我们将产生一系列双突变组合来定义和表征促进延迟和去突触的顺式和反式作用信号。我们对信号级联的两个下游靶进行了详细的功能分析：完整的核膜蛋白SUN-1，它是染色体与核外周相互作用所必需的；以及SYP蛋白，联会复合体蛋白的核心成分。此外，我们将探索初步RNAi筛查中确定的候选信号分子的作用。这些互补的方法将为监测系统提供重要的见解，该系统监测每个染色体上的交叉形成，并允许通过减数分裂及时进行。