THE FORK HEAD TRANSCRIPTION FACTOR DAF-16 TRANSDUCES INSULIN-LIKE METABOLIC AND LONGEVITY SIGNALS IN CAENORHABDITIS-ELEGANS

In mammals, insulin signalling regulates glucose transport together wi th the expression and activity of various metabolic enzymes. In the ne matode Caenorhabditis elegans, a related pathway regulates metabolism, development and longevity(1,2). Wild-type animals enter the developme ntally arrested dauer stage in response to high levels of a secreted p heromone(3), accumulating large amounts of fat in their intestines and hypodermis. Mutants in DAF-2 (a homologue of the mammalian insulin re ceptor) and AGE-1 (a homologue of the catalytic subunit of mammalian p hosphatidylinositol 3-OH kinase) arrest development at the dauer stage (3), Moreover, animals bearing weak or temperature-sensitive mutations in daf-2 and age-1 can develop reproductively, but nevertheless show increased energy storage and longevity(1,2,4,5). Here we show that nul l mutations in daf-16 suppress the effects of mutations in daf-2 or ag e-1; lack of daf-16 bypasses the need for this insulin receptor-like s ignalling pathway. The principal role of DAF-2/AGE-1 signalling is thu s to antagonize DAF-16. daf-16 is widely expressed and encodes three m embers of the Fork head family of transcription factors, The DAF-2 pat hway acts synergistically with the pathway activated by a nematode TGF -beta-type signal, DAF-7, suggesting that DAF-16 cooperates with nemat ode 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 coop erate with TGF-beta effecters in mediating metabolic regulation. These genes may be dysregulated in diabetes.