Abstract:

The insulin/IGF-1 signalling (IIS) pathway has diverse roles from metabolism to longevity^{1, 2, 3, 4, 5}. In Caenorhabditis elegans, the single forkhead box O (FOXO) homologue, DAF-16, functions as the major target of the IIS pathway^{2, 3, 6, 7}. One of two isoforms^{4, 5, 8}, DAF-16a, is known to regulate longevity, stress response and dauer diapause^{8, 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 functions^{6, 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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