Caenorhabditis elegans EAK-3 inhibits dauer arrest via nonautonomous regulation of nuclear DAF-16/FoxO activity

Dev Biol. 2008 Mar 15;315(2):290-302. doi: 10.1016/j.ydbio.2007.12.032. Epub 2008 Jan 3.


Insulin regulates development, metabolism, and lifespan via a conserved PI3K/Akt pathway that promotes cytoplasmic sequestration of FoxO transcription factors. The regulation of nuclear FoxO is poorly understood. In the nematode Caenorhabditis elegans, insulin-like signaling functions in larvae to inhibit dauer arrest and acts during adulthood to regulate lifespan. In a screen for genes that modulate C. elegans insulin-like signaling, we identified eak-3, which encodes a novel protein that is specifically expressed in the two endocrine XXX cells. The dauer arrest phenotype of eak-3 mutants is fully suppressed by mutations in daf-16/FoxO, which encodes the major target of C. elegans insulin-like signaling, and daf-12, which encodes a nuclear receptor regulated by steroid hormones known as dafachronic acids. eak-3 mutation does not affect DAF-16/FoxO subcellular localization but enhances expression of the direct DAF-16/FoxO target sod-3 in a daf-16/FoxO- and daf-12-dependent manner. eak-3 mutants have normal lifespans, suggesting that EAK-3 decouples insulin-like regulation of development and longevity. We propose that EAK-3 activity in the XXX cells promotes the synthesis and/or secretion of a hormone that acts in parallel to AKT-1 to inhibit the expression of DAF-16/FoxO target genes. Similar hormonal pathways may regulate FoxO target gene expression in mammals.

Publication types

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

MeSH terms

  • Alleles
  • Animals
  • Animals, Genetically Modified
  • Base Sequence
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development*
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Nucleus / metabolism
  • Cloning, Molecular
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • DNA Primers / genetics
  • DNA, Helminth / genetics
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation, Developmental
  • Genes, Helminth
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Longevity / genetics
  • Longevity / physiology
  • Models, Biological
  • Mutation
  • Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Caenorhabditis elegans Proteins
  • DNA Primers
  • DNA, Helminth
  • Forkhead Transcription Factors
  • Recombinant Fusion Proteins
  • Transcription Factors
  • daf-16 protein, C elegans
  • Green Fluorescent Proteins
  • Cytochrome P-450 Enzyme System
  • DAF-9 protein, C elegans
  • DAF-2 protein, C elegans
  • Receptor, Insulin