Comparative Genetic Analysis of Hermaphroditism in Caenorhabditis

描述（由申请人提供）：线虫采用多种繁殖策略，通常与它们作为寄生虫或共栖物与其他生物体的特殊联系有关。我们的长期目标是提供线虫繁殖模式进化的详细发育遗传学理解。这是目前唯一可能的模式属秀丽隐杆线虫。秀丽隐杆线虫和秀丽隐杆线虫都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。这需要生殖系特异性的性别决定改变，这样雌性（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，秀丽隐杆线虫主要通过核心通路基因的转录后调控来实现这种调控。最近对C. briggsae的遗传研究表明，令人惊讶的是，这两个物种的雌雄同体通过在保守的核心途径的不同点进行干预来实现自我生殖。本项目将通过鉴定和表征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，在正向遗传筛选中发现的一种新的促精子基因将被克隆并在分子水平上进行表征。其次，一个保守的rna结合蛋白的目标，其在生殖系性别决定中的作用已经分化，将寻求。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，这些蛋白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我生育的控制目标。总体而言，该项目将采用对秀丽隐杆线虫中发育的基因功能进行强大的分析，以检查趋同进化的发育遗传细节。与人类健康相关：Caenorhabditis性别决定通路是hedgehog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，调节这一途径的新模式的发现可能最终具有临床应用价值。此外，一个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分化也发生在哺乳动物的性别决定基因中，从线虫中吸取的经验教训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繁殖至关重要，它们可能最终成为寄生虫特异性抗蠕虫药物的绝佳靶点。

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.