Analysis of checkpoint function in the germ line.

种系检查点功能分析。

• 批准号: 7930683
• 负责人: JOANNE ENGEBRECHT
• 金额: $ 24.07万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7930683
• 关键词: Adult; Aneuploidy; Animals; Apoptosis; Apoptotic; Caenorhabditis elegans; Cell Cycle; Cell Cycle Arrest; Cells; Chromatin Structure; Chromosome Pairing; Chromosomes; Complement; Congenital Abnormality; DNA; DNA Damage; Defect; Detection; Development; Double Strand Break Repair; Down Syndrome; Ensure; Female; Frequencies; Genes; Genome; Germ Cells; Germ Lines; Haploidy; Human; Incidence; Infertility; Klinefelter' s Syndrome; Malignant Neoplasms; Meiosis; Meiotic Recombination; Mitotic; Modeling; Molecular; Molecular Genetics; Monitor; Oocytes; Parents; Pathway interactions; Phase; Pregnancy loss; Process; Production; Proliferating; Proteins; Reproduction; Signal Pathway; Signal Transduction; Somatic Cell; Spontaneous abortion; Synaptonemal Complex; System; Ultraviolet Rays; X Chromosome; base; egg; gene function; human female; insight; irradiation; male; mutant; operation; prevent; public health relevance; repaired; response; sex; sperm cell

DESCRIPTION (provided by applicant): Germ cells are specialized cells that undergo mitotic proliferation followed by meiosis and cellular differentiation to generate haploid gametes for sexual reproduction. Errors in human germ cells are quite common and result in a high frequency of spontaneous abortions and aneuploid progeny (e.g., Down, Turner and Klinefelter's Syndrome). Surprisingly, checkpoint control appears to be less efficient in the human female germ line; it has been proposed that this is one reason for the high frequency of defects associated with human female gametes. Here, we propose to take advantage of the unique structural organization of the Caenorhabditis elegans germ line, the molecular genetics of the system, and the high degree of conservation with genes and pathways in humans to determine the molecular basis for differential germ-line checkpoint function between the sexes. To tackle this important problem, we will use a multi-pronged approach that relies on the strengths of C. elegans as a model for investigating sex-specific germ-line checkpoint function. To that end, we will compare the surveillance mechanisms in operation in the female and male germ lines, and determine how males selectively sense and respond to damage in proliferating germ cells by analyzing known checkpoint mutants, examining the activation state of checkpoint proteins, and by identifying new checkpoint genes. We will determine how males prevent checkpoint-activated germ-line apoptosis and whether such absence leads to a high incidence of aneuploid gametes by monitoring the status of checkpoint and apoptotic proteins and examining the viability of progeny from reciprocal crosses when meiosis is impaired in only one of the sexes. Finally, we will determine how meiotically-induced double strand breaks are repaired on a single X chromosome without eliciting a checkpoint response by monitoring the loading and disassembly of chromosomal axis and central region components of the synaptonemal complex on the male X, probing the relationship between chromatin structure and checkpoint activation, and identifying the molecular machinery that prevents the single X from eliciting a checkpoint response. An understanding of this process in the genetically tractable worm system may provide insight into why human female meiosis has less efficient checkpoint control, contributing to the high rate of errors. These studies will also provide new and important information on general mechanisms of checkpoint control, processes in which defects are central to the developmental of human cancers. PUBLIC HEALTH RELEVANCE: Germ cells form egg and sperm for sexual reproduction. Our studies are aimed at understanding how errors arise during this process. In humans, such errors result in infertility, pregnancy loss and birth defects such as Down Syndrome.

描述（由申请人提供）：生殖细胞是经历有丝分裂增殖的专门细胞，然后是减数分裂和细胞分化，以产生单倍体配子以进行性繁殖。人类生殖细胞中的误差很普遍，导致自发流产和非整倍体后代（例如，Turner，Turner和Klinefelter's综合征）的频率很高。令人惊讶的是，检查点控制在人类女性系中似乎效率较低。有人提出，这是与人配子相关的高频缺陷的原因之一。在这里，我们建议利用秀丽隐杆线虫生殖系的独特结构组织，系统的分子遗传学以及人类中基因和途径的高度保守性，以确定性别之间差异性细菌性检查点功能的分子基础。为了解决这个重要的问题，我们将使用一种多管齐下的方法，该方法依靠秀丽隐杆线虫的优势作为研究性别特定种系检查点功能的模型。为此，我们将比较雌性和男性生殖系中运行中运行中的监视机制，并通过分析已知的检查点突变体，检查检查点蛋白的激活状态以及鉴定新检查点基因，确定男性如何选择性地感知和对增殖生殖细胞的损害做出反应。我们将确定雄性如何通过监测检查点和凋亡蛋白的状态来防止检查点激活的种系细胞凋亡以及这种缺失是否导致非整倍型配子的发生率很高，并检查只有在大性别中减数分裂而损害相互交叉的后代的可行性并检查后代的生存能力。最后，我们将确定如何在单个X染色体上修复减数分裂诱导的双链断裂，而无需通过监测染色体轴上染色体轴的负载和拆卸和拆卸染色体结构和检查点激活的响应之间的关系，并识别单个单身的响应，从而探测了X.在遗传上易于处理的蠕虫系统中对这一过程的理解可能会深入了解为什么人类减数分裂的效率较低，从而导致高误差率。这些研究还将提供有关检查点控制的一般机制的新的重要信息，其中缺陷对人类癌症的发展至关重要。 公共卫生相关性：生殖细胞形成卵子和精子以进行有性繁殖。我们的研究旨在了解此过程中的错误是如何出现的。在人类中，这种错误导致不孕，妊娠丧失和出生缺陷，例如唐氏综合症。