The activity of
daf-2 , which encodes a homolog of insulin and insulin-like growth factor I (IGF-I) receptors (1), is required for non-dauer development and normal adult life span, and is likely to be regulated by one or more insulin-like ligands. By searching the C. elegans genome database, we identified 30 ins genes predicted to encode insulin-like peptides, that could be grouped into several subfamilies on the basis of structural similarities. One gene,
ins-14 on F13B12, contains likely C-peptide cleavage sites typical of mammalian insulins. To investigate whether this family of insulin-related genes could play a role in dauer formation, several members were overexpressed by injecting worms with the appropriate PCR-amplified genomic regions. We hypothesized that overexpression of putative DAF-2 ligands might suppress the Daf-c phenotype of weak
daf-2 mutants or mutants in the parallel
daf-7 TGF-ß pathway, which synergizes with the
daf-2 insulin-like signaling pathway (2). None of the tested genes suppressed
daf-2(
e1365) , a non-null allele, although these transgenic worms may not have produced enough ligand to overcome the impaired DAF-2 receptor. However, the
ins-14 , but not the M04D8.2 or T10D8.a&b, transgene maternally suppressed the Daf-c phenotype of
daf-7(
e1372) . Similar results were seen with an
ins-14 transgene in which the coding region was replaced with the cDNA for human insulin. An
ins-14::GFP transgene is expressed in many neurons, intestine, and vulval muscles. Finally, we isolated a deletion mutant,
ins-14(
nr2091) , in which the entire coding region is removed.
ins-14(
nr2091) had no dauer phenotype as a single mutant, but enhanced the Daf-c phenotype of
daf-7 in the
ins-14(
nr2091);
daf-7(
e1372) double mutant. The suppression of the
daf-7(
e1372) Daf-c phenotype by
ins-14 overexpression and its enhancement by the
ins-14(
nr2091) mutation is consistent with
ins-14 acting as a DAF-2 agonist. Other members of the ins gene family may act either redundantly as agonists or possibly as antagonists of DAF-2. (1) Kimura et al, Science 1997;277:942 (2) Ogg et al, Nature 1997;389:994