Comparative Genetic Analysis of Hermaphroditism in Caenorhabditis

秀丽隐杆线虫雌雄同体的比较遗传学分析

• 批准号: 7318316
• 负责人: ERIC HAAG
• 金额: $ 25.13万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-06 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7318316
• 关键词: Address; Affect; Alleles; Animals; Biochemical Genetics; Biological; Biological Assay; Caenorhabditis; Caenorhabditis elegans; Candidate Disease Gene; Cell Proliferation; Cells; Evolution; Family; Female; Fertility; Fogs; Funding; Gene Family; Gene Targeting; Genes; Genetic; Genetic Screening; Germ Cells; Germ Lines; Goals; Health; Hermaphroditism; Homologous Gene; Human; Human Development; Intervention; Karyotype; Learning; Localized; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; Methods; Modeling; Molecular; Molecular Genetics; Mutation; Nematoda; Organism; Parasites; Pathway interactions; Pharmaceutical Preparations; Post-Transcriptional Regulation; RNA-Binding Proteins; Regulation; Reproduction; Research; Research Personnel; Role; Spermatogenesis; Translations; Tumor Suppressor Genes; Variant; Work; clinical application; comparative; developmental genetics; egg; gene function; genetic analysis; genome sequencing; male; mutant; novel; positional cloning; programs; reproductive; sex; sex determination; smoothened signaling pathway; sperm cell; tool

DESCRIPTION (provided by applicant): Nematodes employ a variety of reproductive strategies, often related to their specialized associations with other organisms as parasites or commensals. Our long-term goal is to provide a detailed developmental genetic understanding of how nematode reproductive modes evolve. This is currently only possible in the model genus Caenorhabditis. Both C. elegans and C. briggsae produce outwardly similar self-fertile hermaphrodites, which evolved in parallel from female ancestors by acquiring limited spermatogenesis. This required germ line-specific changes in sex determination, so that animals with a female (XX) karyotype can nevertheless produce male cells (i.e. sperm). Decades of research have shown that C. elegans accomplishes this regulation primarily through post-transcriptional regulation of core pathway genes. Recent genetic studies in C. briggsae have shown, surprisingly, that the hermaphrodites of these two species achieve self-fertility via intervention at different points in the conserved core pathway. This project will extend this work by identifying and characterizing the function of germline-specific factors in C. briggsae that control XX spermatogenesis. First, a novel sperm-promoting gene identified in a forward genetic screen will be cloned and characterized at the molecular level. Second, targets of a conserved RNA-binding protein whose role in germline sex determination has diverged will be sought. Third, reverse genetic methods will be used to target genes encoding other RNA-binding proteins, which are likely to be important in germline sex determination. Finally, we will study the role of C. briggsae tra-1 in germline sex determination, because it is a likely target of the controls that enable self-fertility. Overall, this project will employ powerful assays for gene function developed in C. elegans to examine the developmental genetic details of convergent evolution. Relevance to human health: The Caenorhabditis sex determination pathway is a variant of the hedgehog signaling pathway, which has important roles in human development and cancer. The discovery of new modes of regulating this pathway may therefore have eventual clinical applications. In addition, a conserved tumor suppressor gene, gld-1, will be a major focus of the project, further connecting the work to cancer. Second, as the rapid sequence divergence seen in this pathway also occurs in mammalian sex determination genes, lessons learned from nematodes may be relevant to human development and fertility. Finally, since these rapidly evolving features are essential for nematode reproduction, they may eventually make excellent targets for parasite-specific anti-helminthic drugs.

描述(由申请人提供)：线虫使用各种繁殖策略，通常与它们与其他生物作为寄生虫或共生体的特殊联系有关。我们的长期目标是为线虫繁殖模式的进化提供详细的发育遗传学理解。目前，这只可能发生在模式线虫属中。线虫和桥线虫都产生外表相似的自育两性，它们是通过获得有限的精子发生而平行地从雌性祖先进化而来的。这就要求在性别决定中对生殖系进行特定的改变，这样具有雌性(XX)核型的动物仍然可以产生雄性细胞(即精子)。几十年的研究表明，线虫主要通过核心途径基因的转录后调节来完成这一调节。最近的遗传学研究表明，令人惊讶的是，这两个物种的两性通过在保守的核心途径上的不同点进行干预而实现了自我繁育。该项目将通过鉴定和表征控制XX精子发生的布里奇萨斯生殖系特异性因子的功能来扩展这项工作。首先，在正向遗传筛查中发现的一种新的促进精子的基因将被克隆并在分子水平上进行表征。其次，将寻找在生殖系性别决定中起不同作用的保守的RNA结合蛋白的靶标。第三，反向遗传方法将被用来针对编码其他RNA结合蛋白的基因，这些蛋白可能在生殖系性别决定中发挥重要作用。最后，我们将研究c.briggsae tra-1在生殖系性别决定中的作用，因为它可能是实现自我繁殖的控制目标。总体而言，该项目将使用在线虫中开发的强大的基因功能分析来检查收敛进化的发育遗传细节。与人类健康相关：线虫性别决定通路是刺猬信号通路的变体，在人类发育和癌症中具有重要作用。因此，调控这一途径的新模式的发现可能最终会在临床上应用。此外，保守的肿瘤抑制基因GLD-1将是该项目的主要焦点，进一步将这项工作与癌症联系起来。其次，由于在这一途径中看到的快速序列差异也发生在哺乳动物的性别决定基因中，从线虫身上学到的经验可能与人类的发育和生育有关。最后，由于这些快速进化的特征对线虫的繁殖至关重要，它们最终可能成为针对寄生虫的抗蠕虫药物的极佳靶标。