Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 6/27/2009
Publication Date: N/A
Citation: N/A Interpretive Summary: N/A
Technical Abstract: How can we complement Caenorhabditis elegans genomics and proteomics with a comprehensive structural and functional annotation of its metabolome? Several lines of evidence indicate that small molecules of largely undetermined structure play important roles in C. elegans biology, including key pathways regulating lifespan, development, and metabolism. We have developed Nuclear Magnetic Resonance (NMR) spectroscopic methodology that enables linking small molecule metabolites directly with corresponding mutant phenotypes and probable biological functions. Application of this approach to identifying the C. elegans mating and dauer pheromones revealed a complex signaling system based on a bi-functional group of signaling molecules, the ascarosides ascr#1-ascr#8. Low concentrations of ascarosides attract males and thus appear to be part of the C. elegans sex pheromone, whereas higher concentrations induce developmental arrest at the dauer stage. Intriguingly, only mixtures of several ascarosides produce strong phenotypes at physiologically relevant concentrations, and individual ascarosides exhibit different though overlapping activity profiles. For example, the ascaroside ascr#2 is a stronger dauer inducer than ascaroside ascr#3, whereas ascr#3 is a stronger male attractant than ascr#2. However, mixtures of ascr#2 and ascr#3 are much more active than either compound alone, and addition of a third component, ascr#8, further increases activity, indicating a synergistic mode of action. Cellular and genetic analyses of ascr#3 suggest the role of both core and sex-specific sensory neurons in regulating the response to this metabolite. Additional studies indicate that different ascarosides act through different neuronal and genetic pathways. These findings present a significant departure from the one-compound one-phenotype paradigm and emphasize the need to develop comprehensive approaches for correlating genome, phenotype, and metabolome.