Comparative Genetic Analysis of Hermaphroditism in Caenorhabditis

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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.