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. 2008 Aug 28;454(7208):1115-8.
doi: 10.1038/nature07168. Epub 2008 Jul 23.

A Blend of Small Molecules Regulates Both Mating and Development in Caenorhabditis Elegans

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A Blend of Small Molecules Regulates Both Mating and Development in Caenorhabditis Elegans

Jagan Srinivasan et al. Nature. .
Free PMC article


In many organisms, population-density sensing and sexual attraction rely on small-molecule-based signalling systems. 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 stage. In addition, adult C. elegans males are attracted to hermaphrodites by a previously unidentified small-molecule signal. 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 formation. 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.


Figure 1
Figure 1. Activity-guided fractionation of worm metabolites
a, Representation of the bioassay used to measure mating behaviour in worms. Crosses mark the initial positions of the assayed animals (see Supplementary Methods).b, Male and hermaphrodite responses to secreted metabolites produced by hermaphrodites at different developmental stages. L1-L4, the first four larval stages; D, dauer stage; YA, young adult stage; A, adult stage; C, control. n≥30 animals for each histogram. c, Assay results for C18-reversed-phase chromatography fractions of young adult metabolite extract. d, Assay results for combinations of ion-exchange fractions of the active fraction from c: A, neutral; B, 250 mM KCl anion; C, 250 mM KCl cation; D, 500 mM KCl anion; E, 500 mM KCl cation; F, 1,000 mM KCl cation; G, 1,000 mM KCl anion. Error bars, s.e.m.; *P<0.01, ***P<0.0001, unpaired t-test (see Supplementary Methods).
Figure 2
Figure 2. Synergy between ascr#2, ascr#3 and ascr#4
a,Structures of ascr#1, ascr#2, ascr#3 and ascr#4. b, Dose-response curves of ascr#2 and ascr#3. c, Synergistic effects of ascr#2 and ascr#3 from points respectively indicated by red and blue arrows in b. d, Demonstration that the three synthetic compounds account for most of the mating activity. For all entries, ascr#4 was tested at 1 pmol and ascr#2 and ascr#3 were each tested at 20 fmol. n≥30 animals for each histogram. Error bars, s.e.m.; *P<0.01, ***P<0.0001, unpaired t-test.
Figure 3
Figure 3. Neurons mediating response to ascr#3
a,Dose-response curve for male reversal rates on plates with increasing concentrations of ascr#3. n≥15 animals for each histogram. Error bars, s.e.m.; *P<0.05, **P<0.01, one-factor analysis of variance with post test. b, Male attraction by ascr#3 in sensory-deficient mutants-. Error bars, s.e.m. c, General sensory neurons and sex-specific neurons mediate response to ascr#3. Ablation of neurons involved in volatile chemotaxis (amphid winged sensory neuron type A (AWA) and amphid winged sensory neuron type C (AWC)) together with the CEM neurons did not affect response to ascr#3, in comparison with animals lacking only CEM neurons. n≥15 animals for each ablation set. Error bars, s.e.m.;*P<0.05, **P<0.01, one-factor analysis of variance with post test.

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