Comparative Genetic Analysis of Hermaphroditism in Caenorhabditis

描述（由申请人提供）：线虫采用多种生殖策略，通常与其与其他生物体（如寄生虫或寄生虫）的专门联系有关。我们的长期目标是提供一个详细的发育遗传学的理解如何线虫生殖模式的演变。目前，这仅在模式属小杆线虫中是可能的。两个C. elegans和C. Briggsae产生外表相似的自育雌雄同体，它们通过获得有限的精子发生而从雌性祖先平行进化而来。这需要性别决定中的生殖系特异性变化，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）。几十年的研究表明，C。秀丽线虫主要通过核心途径基因的转录后调节来实现这种调节。最近的遗传学研究C. Briggsae已经令人惊讶地表明，这两个物种的雌雄同体通过在保守的核心途径中的不同点进行干预来实现自育性。本项目将通过鉴定和表征C. BRIGGSAE控制XX精子发生。首先，一个新的精子促进基因在正向遗传筛选确定将克隆和分子水平上的特点。第二，将寻找在生殖系性别决定中的作用已经分化的保守RNA结合蛋白的靶点。第三，反向遗传学方法将用于靶向编码其他RNA结合蛋白的基因，这些蛋白可能在生殖系性别决定中很重要。最后，我们将研究C的作用。Briggsae TRA-1在生殖系性别决定中的作用，因为它可能是使自身能生育的控制的目标。总的来说，这个项目将采用强大的基因功能分析在C。elegans研究趋同进化的发育遗传细节。与人类健康的相关性：小杆线虫性别决定通路是刺猬信号通路的一种变体，在人类发育和癌症中具有重要作用。因此，发现调节该途径的新模式可能最终具有临床应用。此外，一个保守的肿瘤抑制基因gld-1将成为该项目的主要焦点，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性别决定基因中，从线虫中吸取的教训可能与人类发育和生育有关。最后，由于这些快速进化的功能是线虫繁殖所必需的，它们最终可能成为寄生虫特异性抗蠕虫药物的极好靶点。

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.