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.
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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).
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).
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)).
Kenyon, C. et al. AC. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993).
Larsen, P. L., Albert, P. S. & Riddle, D. L. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics 139, 1567–1583 (1995).
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).
Vowels, J. J. & Thomas, J. H. Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans. Genetics 130, 105–123 (1992).
Patterson, G. I. et al. ASmad protein that acts antagonistically in the C. elegans TGF-β dauer regulatory pathway. Genes Dev.(in the press).
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).
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).
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).
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).
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).
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).
Nojima, T. et al. Acase of alveolar rhabdosarcoma with a chromosomal translocation, t(2;13)q37;q14). Virchows Arch. Path. 417, 357–359 (1990).
Lai, E. et al. HNF-3A, a hepatocyte-enriched transcription factor of novel structure is regulated transcriptionally. Genes Dev. 4, 1427–1436 (1990).
Kaufmann, E., Muller, D. & Knochel, W. DNA recognition site analysis of Xenopus winged helix proteins. J. Mol. Biol. 248, 239–254 (1995).
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).
Larsen, P. Aging and resistance to oxidative damage in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 90, 8905–8909 (1993).
Riddle, D. L., Swanson, M. M. & Albert, P. S. Interacting genes in nematode dauer larva formation. Nature 290, 668–671 (1981).
Toker, A. & Cantley, L. C. Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 387, 673–676 (1997).
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).
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).
Ren, P. et al. Control of C. elegans larval development by neuronal expression of a TGF-β homologue. Science 274, 1389–1391 (1996).
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).
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).
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).
Chen, X., Rubock, M. J. & Whitman, M. Atranscriptional partner for MAD proteins in TGF-β signalling. Nature 383, 691–696 (1996).
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).
Golden, J. W. & Riddle, D. L. Apheromone influences larval development in the nematode Caenorhabditis elegans. Science 218, 578–580 (1982).
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.
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