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

Jason M. Held, Mark P. White, Alfred L. Fisher, Bradford W. Gibson, Gordon J. Lithgow, Matthew S. Gill

Research output: Contribution to journalArticle

47 Scopus citations

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-3β-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 Δ5-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.

Original languageEnglish (US)
Pages (from-to)283-291
Number of pages9
JournalAging cell
Volume5
Issue number4
DOIs
StatePublished - Aug 2006

Keywords

  • C. elegans
  • DAF-12
  • Dauer
  • Ligand
  • Lipid
  • Nuclear receptor

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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