Nature 454, 1115-1118 (28 August 2008) | doi:10.1038/nature07168; Received 17 January 2008; Accepted 13 June 2008; Published online 23 July 2008

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

Jagan Srinivasan1,7, Fatma Kaplan2,3,4,7, Ramadan Ajredini2,3,4, Cherian Zachariah2,3,4, Hans T. Alborn5, Peter E. A. Teal5, Rabia U. Malik6, Arthur S. Edison2,3,4, Paul W. Sternberg1 & Frank C. Schroeder6

  1. Howard Hughes Medical Institute and Biology Division, California Institute of Technology, 1200 E. California Boulevard, Pasadena, California 91125, USA
  2. Department of Biochemistry and Molecular Biology,
  3. McKnight Brain Institute,
  4. National High Magnetic Field Laboratory, University of Florida, PO Box 100245, Gainesville, Florida 32610-0245, USA
  5. Center for Medical, Agricultural and Veterinary Entomology, USDA-ARS, 1600–1700 SW 23rd Drive, PO Box 14565, Gainesville, Florida 32604, USA
  6. Boyce Thompson Institute, Cornell University, Ithaca, New York 14853, USA
  7. These authors contributed equally to this work.

Correspondence to: Arthur S. Edison2,3,4Paul W. Sternberg1Frank C. Schroeder6 Correspondence and requests for materials should be addressed to P.W.S. (Email: pws@caltech.edu), F.C.S. (Email: fs31@cornell.edu) or A.S.E. (Email: art@mbi.ufl.edu).

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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