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.

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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.

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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.

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Correspondence to Gary Ruvkun.

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