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A blend of small molecules regulates both mating and development in Caenorhabditis elegans


In many organisms, population-density sensing and sexual attraction rely on small-molecule-based signalling systems1,2. In the nematode Caenorhabditis elegans, population density is monitored through specific glycosides of the dideoxysugar ascarylose (the ‘ascarosides’) that promote entry into an alternative larval stage, the non-feeding and highly persistent dauer stage3,4. In addition, adult C. elegans males are attracted to hermaphrodites by a previously unidentified small-molecule signal5,6. Here we show, by means of combinatorial activity-guided fractionation of the C. elegans metabolome, that the mating signal consists of a synergistic blend of three dauer-inducing ascarosides, which we call ascr#2, ascr#3 and ascr#4. This blend of ascarosides acts as a potent male attractant at very low concentrations, whereas at the higher concentrations required for dauer formation the compounds no longer attract males and instead deter hermaphrodites. The ascarosides ascr#2 and ascr#3 carry different, but overlapping, information, as ascr#3 is more potent as a male attractant than ascr#2, whereas ascr#2 is slightly more potent than ascr#3 in promoting dauer formation7. We demonstrate that ascr#2, ascr#3 and ascr#4 are strongly synergistic, and that two types of neuron, the amphid single-ciliated sensory neuron type K (ASK) and the male-specific cephalic companion neuron (CEM), are required for male attraction by ascr#3. On the basis of these results, male attraction and dauer formation in C. elegans appear as alternative behavioural responses to a common set of signalling molecules. The ascaroside signalling system thus connects reproductive and developmental pathways and represents a unique example of structure- and concentration-dependent differential activity of signalling molecules.

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Figure 1: Activity-guided fractionation of worm metabolites.
Figure 2: Synergy between ascr#2, ascr#3 and ascr#4.
Figure 3: Neurons mediating response to ascr#3.


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This work was supported by the Human Frontiers Science Program (A.S.E., P.W.S. and P.E.A.T.), a US National Institutes of Health grant (P41 GM079571) to F.C.S., and the Howard Hughes Medical Institute, of which J.S. is an associate and P.W.S. an investigator. NMR data were collected in the UF-AMRIS facility; we thank J. Rocca for assistance. We thank E. Peden and D. Xue for the ceh-30 strains, C. J. Cronin and A. Choe for advice on behavioural assays, L. R. Baugh for liquid-culture dauer formation assays, B. Fox for assistance with the synthesis of ascr#2, ascr#3 and ascr#4, and M. de Bono, A. Dossey and M. Stadler for discussions. E. Hallem, J. Bungert and D. Hutchinson provided comments on the manuscript.

Author Contributions J.S. and P.W.S. designed the biological experiments and J.S. performed all the biological experiments; F.K. developed the procedure for collecting secreted worm metabolites and designed the chemical experiments and fractionation; F.K. and R.A. produced worm-conditioned water and performed chromatography; F.K., F.C.S., R.U.M., C.Z. and A.S.E. performed structure elucidation by NMR; H.T.A. performed structure elucidation by LC-MS; F.C.S. synthesized ascr#2, ascr#3 and ascr#4; and J.S., F.K., F.C.S., A.S.E., P.E.A.T. and P.W.S. analysed the data and wrote the paper.

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Correspondence to Arthur S. Edison, Paul W. Sternberg or Frank C. Schroeder.

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Srinivasan, J., Kaplan, F., Ajredini, R. et al. A blend of small molecules regulates both mating and development in Caenorhabditis elegans. Nature 454, 1115–1118 (2008).

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