DAF-12-dependent rescue of dauer formation in Caenorhabditis elegans by (25S)-cholestenoic acid

Aging Cell. 2006 Aug;5(4):283-91. doi: 10.1111/j.1474-9726.2006.00218.x.

Abstract

Population density, temperature and food availability all regulate the formation of the Caenorhabditis elegans dauer larva by modulating endocrine signaling pathways. The orphan nuclear receptor DAF-12 is pivotal for the decision to form a dauer or to undergo normal reproductive development. The DAF-12 ligand has been predicted to be a sterol that is metabolized by DAF-9, a cytochrome P450. Here we chemically characterize purified lipophilic nematode extracts and show that the ligand for DAF-12 contains a carboxyl moiety and is likely to be derived from a sterol. Using a candidate ligand approach we find that the C27 bile acid cholestenoic acid (5-cholesten-3beta-ol-(25S)-carboxylic acid) promotes reproductive growth in dauer-constitutive mutants in a daf-9- and daf-12-dependent manner. Furthermore, we find that cholestenoic acid can act as a DAF-12 ligand by activating DAF-12 in a cell-based transcription assay. Analysis of dauer-rescuing lipophilic extracts from nematodes by gas chromatography-mass spectrometry indicates the presence of several regioisomers of cholestenoic acid that are distinct from Delta(5)-cholestenoic acid and are not present in extracts from daf-9 mutants. These data suggest that carboxylated sterols may be key determinants of life history.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Line
  • Cholestenes / pharmacology
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Developmental
  • Humans
  • Larva / metabolism
  • Larva / physiology*
  • Ligands
  • Mutation
  • Phenotype
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Transfection

Substances

  • Caenorhabditis elegans Proteins
  • Cholestenes
  • DAF-12 protein, C elegans
  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • cholestenoic acid
  • Cytochrome P-450 Enzyme System
  • DAF-9 protein, C elegans