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: 8065400
• 负责人: ERIC HAAG
• 金额: $ 25.24万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065400
• 关键词: Address; Affect; Alleles; Animals; Biochemical; Biological; Biological Assay; Caenorhabditis; Caenorhabditis elegans; Candidate Disease Gene; Cell Proliferation; Cells; Evolution; 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; 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; Protein Family; RNA-Binding Proteins; Regulation; Reproduction; Research; Research Personnel; Role; Spermatogenesis; Translations; Tumor Suppressor Genes; Variant; Work; cell fate specification; 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）：线虫采用多种繁殖策略，通常与它们与其他生物（如寄生虫或共生体）的特殊联系有关。我们的长期目标是提供关于线虫繁殖模式如何进化的详细发育遗传学理解。目前，这仅在模式秀丽隐杆线虫属中是可能的。线虫和布里格斯线虫都产生外观相似的自体受精雌雄同体，它们通过获得有限的精子发生从雌性祖先平行进化而来。这需要性别决定方面发生生殖系特异性变化，因此具有雌性（XX）核型的动物仍然可以产生雄性细胞（即精子）。数十年的研究表明，秀丽隐杆线虫主要通过核心途径基因的转录后调节来完成这种调节。最近对 C. briggsae 的遗传学研究令人惊讶地表明，这两个物种的雌雄同体通过对保守核心途径的不同点进行干预来实现自体受精。该项目将通过识别和表征 C. briggsae 中控制 XX 精子发生的种系特异性因子的功能来扩展这项工作。首先，在正向遗传筛选中鉴定出的新型精子促进基因将被克隆并在分子水平上进行表征。其次，将寻找一种保守的RNA结合蛋白的靶标，该蛋白在种系性别决定中的作用已经发生了变化。第三，反向遗传方法将用于靶向编码其他RNA结合蛋白的基因，这可能在种系性别决定中很重要。最后，我们将研究 C. briggsae tra-1 在种系性别决定中的作用，因为它可能是实现自体受孕的控制目标。总体而言，该项目将采用在线虫中开发的强大基因功能分析方法来检查趋同进化的发育遗传细节。与人类健康的相关性：秀丽隐杆线虫性别决定通路是刺猬信号通路的一个变体，在人类发育和癌症中具有重要作用。因此，调节该途径的新模式的发现可能具有最终的临床应用。此外，保守的肿瘤抑制基因gld-1将成为该项目的重点，进一步将这项工作与癌症联系起来。其次，由于该途径中看到的快速序列分歧也发生在哺乳动物性别决定基因中，因此从线虫中吸取的教训可能与人类发育和生育能力有关。最后，由于这些快速进化的特征对于线虫繁殖至关重要，因此它们最终可能成为寄生虫特异性抗蠕虫药物的极好靶标。

项目成果

Intense sperm-mediated sexual conflict promotes reproductive isolation in Caenorhabditis nematodes.

• DOI: 10.1371/journal.pbio.1001915
• 发表时间: 2014-07
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Ting JJ;Woodruff GC;Leung G;Shin NR;Cutter AD;Haag ES
• 通讯作者: Haag ES

Simplification and desexualization of gene expression in self-fertile nematodes.

• DOI: 10.1016/j.cub.2012.09.038
• 发表时间: 2012-11-20
• 期刊: CURRENT BIOLOGY
• 影响因子: 9.2
• 作者: Thomas, Cristel G.;Li, Renhua;Smith, Harold E.;Woodruff, Gavin C.;Oliver, Brian;Haag, Eric S.
• 通讯作者: Haag, Eric S.

Causes and consequences of the evolution of reproductive mode in Caenorhabditis nematodes.

线虫生殖方式进化的原因和后果。

• DOI: 10.1016/j.tig.2012.02.007
• 发表时间: 2012
• 期刊: Trends in genetics : TIG
• 作者: Thomas,CristelG;Woodruff,GavinC;Haag,EricS
• 通讯作者: Haag,EricS

A sensitized genetic background reveals evolution near the terminus of the Caenorhabditis germline sex determination pathway.

• DOI: 10.1111/j.1525-142x.2009.00340.x
• 发表时间: 2009-07
• 期刊: Evolution & development
• 影响因子: 2.9
• 作者: Hill RC;Haag ES
• 通讯作者: Haag ES

Evolutionarily dynamic roles of a PUF RNA-binding protein in the somatic development of Caenorhabditis briggsae.

PUF RNA 结合蛋白在 Caenorhabditis briggsae 体细胞发育中的进化动态作用。

• DOI: 10.1002/jez.b.22550
• 发表时间: 2014
• 期刊: Journal of experimental zoology. Part B, Molecular and developmental evolution
• 作者: Liu,Qinwen;Haag,EricS
• 通讯作者: Haag,EricS