Natural and Synthetic Small-Molecule Modulators of Dauer Development in Nematodes

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In Caenorhabditis elegans and related nematodes, the dauer pheromone is the primary cue for entry into the developmentally arrested, dauer larval stage, and Its activity is antagonized by an uncharacterized 'food signal'. Similar in many respects to a quorum-sensing molecule, the dauer pheromone is constitutively secreted into the environment by the nematode, and thus enables the nematode to sense its population density. Dauer pheromone and food signal are thought to modulate the TGFp and insulin/IGF-1 pathways, which regulate dauer development and also control metabolism and aging in C. elegans arid in higher organisms. Several components of the dauer pheromone have been Identified as derivatives of the dideoxy sugar ascarylose, but additional unidentified components of the dauer pheromone contribute to its activity. Furthermore, the components that are produced vary depending on environmental conditions. In order to investigate the nature ofthe dauer pheromone, we will 1) identify the chemical structures of all active components ofthe dauer pheromone and the environmental conditions that modulate their production, 2) investigate their mechanism of action using epistasis analysis, 3) investigate their biosynthesis by characterization of biosynthetic mutants and by performing a candidate RNAi screen for additional biosynthetic genes, and 4) identify the chemical structures and cross-species activities of the dauer pheromone from several related nematode species. In order to characterize the food signal that antagonizes the dauer pheromone, we will identify Its chemical structure and investigate its mechanism of action using epistasis analysis. Lastly, in order to identify synthetic small molecules that target the TGFp and insulin/IGF- 1 pathways, we will perform a high-throughput screen for molecules that either suppress dauer formation or induce dauer recovery. This screen could potentially identify novel anthelmintics. In summary, identifying the dauer pheromone and the food signal and characterizing their mechanism of action are critical to our understanding of how chemosensory cues from the environment can influence such fundamental processes as development, metabolism, and aging in nematodes and in higher organisms.