Abstract
The insulin/IGF-1 signalling (IIS) pathway has diverse roles from metabolism to longevity1,2,3,4,5. In Caenorhabditis elegans, the single forkhead box O (FOXO) homologue, DAF-16, functions as the major target of the IIS pathway2,3,6,7. One of two isoforms4,5,8, DAF-16a, is known to regulate longevity, stress response and dauer diapause8,9,10,11. However, it remains unclear how DAF-16 achieves its specificity in regulating these various biological processes. Here we identify a new isoform, DAF-16d/f, as an important isoform regulating longevity. We show that DAF-16 isoforms functionally cooperate to modulate IIS-mediated processes through differential tissue enrichment, preferential modulation by upstream kinases, and regulating distinct and overlapping target genes. Promoter-swapping experiments show both the promoter and the coding region of DAF-16 are important for its function. Importantly, in mammals, four FOXO genes have overlapping and different functions6,12, and in C. elegans, a single FOXO/DAF-16 uses distinct isoforms to fine-tune the IIS-mediated processes in the context of a whole organism.
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References
Calnan, D. R. & Brunet, A. The FoxO code. Oncogene 27, 2276–2288 (2008)
Antebi, A. Genetics of aging in Caenorhabditis elegans . PLoS Genet. 3, e129 (2007)
Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010)
Lin, K., Dorman, J. B., Rodan, A. & Kenyon, C. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans . Science 278, 1319–1322 (1997)
Ogg, 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)
Narasimhan, S. D., Yen, K. & Tissenbaum, H. A. Converging pathways in lifespan regulation. Curr. Biol. 19, R657–R666 (2009)
Mukhopadhyay, A., Oh, S. W. & Tissenbaum, H. A. Worming pathways to and from DAF-16/FOXO. Exp. Gerontol. 41, 928–934 (2006)
Lin, K., Hsin, H., Libina, N. & Kenyon, C. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nature Genet. 28, 139–145 (2001)
Henderson, S. T. & Johnson, T. E. daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans . Curr. Biol. 11, 1975–1980 (2001)
Lee, R. Y., Hench, J. & Ruvkun, G. Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr. Biol. 11, 1950–1957 (2001)
Libina, N., Berman, J. R. & Kenyon, C. Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell 115, 489–502 (2003)
Arden, K. C. FOXO animal models reveal a variety of diverse roles for FOXO transcription factors. Oncogene 27, 2345–2350 (2008)
Oh, S. W. et al. JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc. Natl Acad. Sci. USA 102, 4494–4499 (2005)
Lehtinen, M. K. et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 125, 987–1001 (2006)
Berdichevsky, A., Viswanathan, M., Horvitz, H. R. & Guarente, L. C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell 125, 1165–1177 (2006)
Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004)
Lee, S. S., Kennedy, S., Tolonen, A. C. & Ruvkun, G. DAF-16 target genes that control C. elegans life-span and metabolism. Science 300, 644–647 (2003)
McElwee, J., Bubb, K. & Thomas, J. H. Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell 2, 111–121 (2003)
Murphy, C. T. et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans . Nature 424, 277–283 (2003)
Herman, R. K. Mosaic analysis. Methods Cell Biol. 48, 123–146 (1995)
Padmanabhan, S. et al. A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation. Cell 136, 939–951 (2009)
Riddle, D. L. & Albert, P. S. in C. elegans II (eds Riddle, D. L., Blumenthal, T., Meyer, B. J. & Priess, J. R.) 739–768 (Cold Spring Harbor Laboratory Press, 1997)
Honda, Y. & Honda, S. The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans . FASEB J. 13, 1385–1393 (1999)
Murakami, S. & Johnson, T. E. A genetic pathway conferring life extension and resistance to UV stress in Caenorhabditis elegans . Genetics 143, 1207–1218 (1996)
Kimura, K. D., Tissenbaum, H. A., Liu, Y. & Ruvkun, G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans . Science 277, 942–946 (1997)
Soukas, A. A., Kane, E. A., Carr, C. E., Melo, J. A. & Ruvkun, G. Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans . Genes Dev. 23, 496–511 (2009)
Oh, S. W. et al. Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation. Nature Genet. 38, 251–257 (2005)
Stiernagle, T. Maintenance of C. elegans . WormBook 10.1895/wormbook.1.101.1 (2006)
Hosono, R., Mitsui, Y., Sato, Y., Aizawa, S. & Miwa, J. Life span of the wild and mutant nematode Caenorhabditis elegans. Effects of sex, sterilization, and temperature. Exp. Gerontol. 17, 163–172 (1982)
Mello, C. C., Kramer, J. M., Stinchcomb, D. & Ambros, V. Efficient gene transfer in C. elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J. 10, 3959–3970 (1991)
Acknowledgements
We are grateful to A. Mukhopadhyay and S. Padmanabhan for advice, M. Green and M. Walhout for advice and comments on the manuscript and N. Bhabhalia for technical support. We thank M. Grabowski Auclair for generating several strains used in this manuscript and G. Ruvkun and M. Walhout for plasmids and strains. We apologize to all those whose original work was not cited because of space limitations. Some of the strains were provided by T. Stiernagle at the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health National Center for Research Resources. H.A.T. is a William Randolph Hearst Young Investigator. This project was funded in part by grants from the National Institute of Aging AG025891 and AG031237), the Glenn Foundation for Medical Research, the Ellison Medical Foundation and an endowment from the William Randolph Hearst Foundation.
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E.-S.K. and H.A.T. designed the experiments and analysed the data. E.-S.K., S.D.N. and K.Y. performed the experiments. E.-S.K., S.D.N., K.Y. and H.A.T. wrote the manuscript.
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Kwon, ES., Narasimhan, S., Yen, K. et al. A new DAF-16 isoform regulates longevity. Nature 466, 498–502 (2010). https://doi.org/10.1038/nature09184
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DOI: https://doi.org/10.1038/nature09184
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