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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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.
The authors declare no competing financial interests.
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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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