Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans

Abstract

In mammals, insulin signalling regulates glucose transport together with the expression and activity of various metabolic enzymes. In the nematode Caenorhabditis elegans, a related pathway regulates metabolism, development and longevity1,2. Wild-type animals enter the developmentally arrested dauer stage in response to high levels of a secreted pheromone3, accumulating large amounts of fat in their intestines and hypodermis. Mutants in DAF-2 (a homologue of the mammalian insulin receptor) and AGE-1 (a homologue of the catalytic subunit of mammalian phosphatidylinositol 3-OH kinase) arrest development at the dauer stage3. Moreover, animals bearing weak or temperature-sensitive mutations in daf-2 and age-1 can develop reproductively, but nevertheless show increased energy storage and longevity1,2,4,5. Here we show that null mutations in daf-16 suppress the effects of mutations in daf-2 or age-1; lack of daf-16 bypasses the need for this insulin receptor-like signalling pathway. The principal role of DAF-2/AGE-1 signalling is thus to antagonize DAF-16. daf-16 is widely expressed and encodes three members of the Fork head family of transcription factors. The DAF-2 pathway acts synergistically with the pathway activated by a nematode TGF-β-type signal, DAF-7, suggesting that DAF-16 cooperates with nematode SMAD proteins in regulating the transcription of key metabolic and developmental control genes. The probable human orthologues of DAF-16, FKHR and AFX, may also act downstream of insulin signalling and cooperate with TGF-β effectors in mediating metabolic regulation. These genes may be dysregulated in diabetes.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Metabolic control by daf-16 and daf-3.
Figure 2: daf-16 encodes a Fork head/HNF3-related transcription factor.
Figure 3
Figure 4: Model for regulation of dauer formation by convergent transcriptional outputs from insulin receptor-like and TGF-β-like signal tran.

Similar content being viewed by others

References

  1. Kimura, K. D. et al. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277, 942–946 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Morris, J. Z., Tissenbaum, H. A. & Ruvkun, G. Aphosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382, 536–539 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Riddle, D. L. Genetic and environmental regulation of dauer larva development in C. elegans II, (eds Riddle, D. L. et al.) 739–768 (Cold Spring Harbor Press, NY, (1997)).

  4. Kenyon, C. et al. AC. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993).

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Larsen, P. L., Albert, P. S. & Riddle, D. L. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics 139, 1567–1583 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Gottlieb, S. & Ruvkun, G. daf-2, daf-16, and daf-23: Genetically interacting genes controlling dauer formation in C. elegans. Genetics 137, 107–120 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Vowels, J. J. & Thomas, J. H. Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans. Genetics 130, 105–123 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Patterson, G. I. et al. ASmad protein that acts antagonistically in the C. elegans TGF-β dauer regulatory pathway. Genes Dev.(in the press).

  9. Clark, K. L. et al. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature 364, 412–420 (1993).

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Galili, N. et al. Fusion of a fork head domain to PAX-3 in the solid tumor alveolar rhabdomyosarcoma. Nature Genet. 5, 230–235 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Borkhardt, A. et al. Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23). Oncogene 14, 195–202 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Federicks, W. J. et al. The PAX3-FKHR fusion protein created by the t(2;13) translocation in alveolar rhabdomyosarcomas in a more potent transcriptional activator than PAX3. Mol. Cell. Biol. 15, 1522–1535 (1995).

    Article  Google Scholar 

  13. Kalebic, T., Tsokos, M. & Helman, L. J. In vivo treatment with antibody against IGF-1 receptor suppresses growth of human rhabdomyosarcoma and down-regultes p34cdc2. Cancer Res. 54, 5531–5534 (1994).

    CAS  PubMed  Google Scholar 

  14. Shapiro, D. N. et al. Antisense-mediated reduction in insulin-like growth factor-I receptor expression suppresses the malignant phenotype of a human alveolar rhabdomyosarcoma. J. Clin. Invest. 94, 1235–1242 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nojima, T. et al. Acase of alveolar rhabdosarcoma with a chromosomal translocation, t(2;13)q37;q14). Virchows Arch. Path. 417, 357–359 (1990).

    Article  CAS  Google Scholar 

  16. Lai, E. et al. HNF-3A, a hepatocyte-enriched transcription factor of novel structure is regulated transcriptionally. Genes Dev. 4, 1427–1436 (1990).

    Article  CAS  PubMed  Google Scholar 

  17. Kaufmann, E., Muller, D. & Knochel, W. DNA recognition site analysis of Xenopus winged helix proteins. J. Mol. Biol. 248, 239–254 (1995).

    CAS  PubMed  Google Scholar 

  18. Dorman, J. B. et al. The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans. Genetics 141, 1399–1406 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Larsen, P. Aging and resistance to oxidative damage in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 90, 8905–8909 (1993).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  20. Riddle, D. L., Swanson, M. M. & Albert, P. S. Interacting genes in nematode dauer larva formation. Nature 290, 668–671 (1981).

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Toker, A. & Cantley, L. C. Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 387, 673–676 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Tanti, J. F. et al. Overexpression of a constitutively active form of phosphatidylinositol 3-kinase is sufficient to promote Glut4 translocation in adipocytes. J. Biol. Chem. 271, 25227–25232 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Miller, L. M. et al. lin-31, a Caenorhabditis elegans HNF-3/fork head transcription factor homolog, specieis three alternative cell fates in vulval development. Genes Dev 7, 933–947 (1993).

    Article  CAS  PubMed  Google Scholar 

  24. Ren, P. et al. Control of C. elegans larval development by neuronal expression of a TGF-β homologue. Science 274, 1389–1391 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  25. Georgi, L. L., Albert, P. S. & Riddle, D. L. daf-1, a C. elegans gene controlling dauer larva development, encodes a novel receptor protein kinase. Cell 61, 635–645 (1990).

    Article  CAS  PubMed  Google Scholar 

  26. Estevez, M. et al. The daf-4 gene encodes a bone morphogenetic protein receptor controlling C. elegans dauer larva development. Nature 365, 644–649 (1993).

    Article  ADS  CAS  PubMed  Google Scholar 

  27. Green, J. B., New, H. V. & Smith, J. C. Responses of embryonic Xenopus cells to activin and FGF are separated by multiple dose thresholds and correspond to distinct axes of the mesoderm. Cell 71, 731–739 (1992).

    Article  CAS  PubMed  Google Scholar 

  28. Chen, X., Rubock, M. J. & Whitman, M. Atranscriptional partner for MAD proteins in TGF-β signalling. Nature 383, 691–696 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  29. O'Brien, R. M. et al. Hepatic nuclear factor 3- and hormone-regulated expression of the phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein 1 genes. Mol. Cell. Biol. 15, 1747–1758 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Golden, J. W. & Riddle, D. L. Apheromone influences larval development in the nematode Caenorhabditis elegans. Science 218, 578–580 (1982).

    Article  ADS  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank S. Chissoe, A. Coulson and the C. elegans genome sequencing consortium for sending clones and information and for their help; Y. Liu and F. Lam for technical assistance; Y. Kohara for cDNA clones; R. Barstead for the RB1 and RB2 cDNA libraries; and members of G.R.'s laboratory for discussion and for comments on the manuscript. Some of the strains were provided by the C. elegans Genetics Center which is supported by the national Center for Research Resources. This work was supported by a grant from the NIH.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gary Ruvkun.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ogg, S., Paradis, S., Gottlieb, S. et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389, 994–999 (1997). https://doi.org/10.1038/40194

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/40194

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing