Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C-elegans insulin gene family

The activity of the DAF-2 insulin-like receptor is required for Caenorhabdi tis elegans reproductive growth and normal adult life span. Informatic anal ysis identified 37 C. elegans genes predicted to encode insulin-like peptid es. Many of these genes are divergent insulin superfamily members, and many are clustered, indicating recent diversification of the family. The ins ge nes are primarily expressed in neurons, including sensory neurons, a subset of which are required for reproductive development. Structural predictions and likely C-peptide cleavage sites typical of mammalian insulins suggest that ins-1 is most closely related to insulin. Overexpression of ins-1, or expression of human insulin under the control of ins-1 regulatory sequences , causes partially penetrant arrest at the dauer stage and enhances dauer a rrest in weak daf-2 mutants, suggesting that INS-1 and human insulin antago nize DAF-2 insulin-like signaling. A deletion of the ins-1 coding region do es not enhance or suppress dauer arrest, indicating a functional redundancy among the 37 ins genes. Of five other ins genes tested, the only other one bearing a predicted C peptide also antagonizes daf-e signaling, whereas fo ur ins genes without a C peptide do not, indicating functional diversity wi thin the ins family.