Social and solitary feeding behaviour in wild isolates of C. elegans are associated with two isoforms of the putative neuropeptide receptor NPR-1 that differ at a single residue1. Social feeders encode NPR-1 215F, whereas solitary feeders encode NPR-1 215V. Both receptor isoforms inhibit social feeding, but the genetically dominant NPR-1 215V isoform does so more potently1. To explore how the two NPR-1 receptor isoforms differ functionally we sought to identify their ligands. We screened Xenopus oocytes expressing each receptor isoform with synthetic neuropeptides predicted from the C. elegans genome2. The FaRP (FMRFamide-related peptide) encoded by the
flp-21 gene activated both receptors. A second group of FaRPs encoded by
flp-18 also activated NPR-1 215V, but not NPR-1 215F. To provide further electrophysiological evidence that
flp-21 and
flp-18 encode endogenous NPR-1 ligands, we examined their effects on pharynxes expressing NPR-1 215V. We found that FLP-21 and FLP-18 peptides, but not other tested peptides, significantly inhibited the action potential frequency of NPR-1 215V expressing pharynxes, compared to non-expressing controls. To test genetically if
flp-21 regulates social feeding behaviour, we overexpressed
flp-21 from its own promoter.
flp-21 overexpression induced solitary feeding in wild social C. elegans strains, but not in
npr-1(null) mutants, consistent with FLP-21 being an endogenous NPR-1 215F ligand. As predicted, a
flp-21 deletion mutant enhanced the aggregation behaviour of
npr-1 215F animals. However the mutation induced only very weak social behaviour in
npr-1 215V animals, consistent with activation of the NPR-1 215V receptor by both
flp-21 and non-
flp-21 encoded ligands. We predict the non-
flp-21 ligands would be encoded by
flp-18.
flp-18 and
flp-21 are expressed in a small number of identified head neurons. Thus solitary feeding may have evolved in C. elegans by a gain-of-function F-to-V change at residue 215 of NPR-1 that altered ligand response. From an evolutionary perspective, the genetically dominant NPR-1 215V allele appears to be derived, since wild isolates of C. briggsae, C. remanei and C. sp CB5161 all encode only NPR-1 215F. 1de Bono M., and Bargmann, C., 1998, Cell 94: 679-689; 2Li, C., Kim, K., and Nelson, L. 1999, Brain Research 848: 26-34.