Functional divergence of dafachronic acid pathways in the control of C. elegans development and lifespan

Dev Biol. 2010 Apr 15;340(2):605-12. doi: 10.1016/j.ydbio.2010.02.022. Epub 2010 Feb 21.


Steroid hormone and insulin/insulin-like growth factor signaling (IIS) pathways control development and lifespan in the nematode Caenorhabditis elegans by regulating the activity of the nuclear receptor DAF-12 and the FoxO transcription factor DAF-16, respectively. The DAF-12 ligands Delta(4)- and Delta(7)-dafachronic acid (DA) promote bypass of the dauer diapause and proper gonadal migration during larval development; in adults, DAs influence lifespan. Whether Delta(4)- and Delta(7)-DA have unique biological functions is not known. We identified the 3-beta-hydroxysteroid dehydrogenase (3betaHSD) family member HSD-1, which participates in Delta(4)-DA biosynthesis, as an inhibitor of DAF-16/FoxO activity. Whereas IIS promotes the cytoplasmic sequestration of DAF-16/FoxO, HSD-1 inhibits nuclear DAF-16/FoxO activity without affecting DAF-16/FoxO subcellular localization. Thus, HSD-1 and IIS inhibit DAF-16/FoxO activity via distinct and complementary mechanisms. In adults, HSD-1 was required for full lifespan extension in IIS mutants, indicating that HSD-1 interactions with IIS are context-dependent. In contrast to the Delta(7)-DA biosynthetic enzyme DAF-36, HSD-1 is dispensable for proper gonadal migration and lifespan extension induced by germline ablation. These findings provide insights into the molecular interface between DA and IIS pathways and suggest that Delta(4)- and Delta(7)-DA pathways have unique as well as overlapping biological functions in the control of development and lifespan.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / physiology*
  • Cholestenes / metabolism*
  • Gene Expression Regulation, Developmental*
  • Genes, Helminth
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Longevity / genetics
  • Longevity / physiology*
  • Models, Biological
  • Mutation
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / physiology
  • Transgenes


  • Cholestenes
  • Recombinant Fusion Proteins
  • dafachronic acid
  • Green Fluorescent Proteins