The
daf-2 insulin-like receptor pathway regulates development and lifespan in Caenorhabditis elegans. Reduced DAF-2 signaling leads to changes in downstream targets via the
daf-16 gene, a fork-head transcription factor which is regulated by DAF-2, and results in extended life-span. Here, we describe the first identification of genes whose expression is controlled by the DAF-2 signaling cascade.
dao-1,
dao-2,
dao-3,
dao-4,
dao-8 and
dao-9 are down-regulated
daf-2 mutant adults compared to wild-type adults, zwhereas
dao-5,
dao-6 and
dao-7 are up-regulated. The latter genes are negatively regulated by DAF-2 signaling and positively regulated by DAF-16. Positive regulation by DAF-2 on
dao-1,
dao-4 and
dao-8 was mediated by DAF-16, whereas
daf-16 mediates only part of DAF-2 signaling for
dao-2 and
dao-9. Regulation by DAF-2 is most likely DAF-16 independent for
dao-3 and
hsp-90. RNA levels of
dao-5 and
dao-6 showed elevated expression in
daf-2 adults, as well as being strongly expressed in dauer larvae. In contrast,
hsp-90 transcript levels are low in
daf-2 mutant adults though they are enriched in dauer larvae, indicating overlapping but not identical mechanisms of efficient life maintenance in stress-resistant dauer larvae and long-lived
daf-2 mutant adults.
dao-1,
dao-8 and
dao-9 are homologs of the FK506 binding proteins that interact with the mammalian insulin pathway.
dao-3 encodes a putative methylenetetrahydrofolate dehydrogenase. DAO-5 shows 33% identity with human nucleolar phosphoprotein P130.
dao-7 is similar to the mammalian ZFP36 protein. Distinct regulatory patterns of dao genes implicate their diverse positions within the signaling network of DAF-2 pathway, and suggest they have unique contributions to development, metabolism and longevity.