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Vol. 15, No. 6, pp. 672-686, March 15, 2001
1 Department of Molecular Biology, Massachusetts General
Hospital and Department of Genetics, Harvard Medical School, Boston,
Massachusetts 02114, USA; 2 Exelixis Pharmaceuticals, Inc.,
South San Francisco, California 94080, USA; 3 Axys Pharmaceuticals,
NemaPharm Group, South San Francisco, California 94080, USA
The activity of the DAF-2 insulin-like receptor is required for
Caenorhabditis elegans reproductive growth and normal adult life span. Informatic analysis identified 37 C. elegans genes predicted to encode insulin-like peptides. Many of these genes are
divergent insulin superfamily members, and many are clustered, indicating recent diversification of the family. The ins genes 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 arrest in weak
daf-2 mutants, suggesting that INS-1 and human insulin
antagonize DAF-2 insulin-like signaling. A deletion of the
ins-1 coding region does 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-2 signaling, whereas
four ins genes without a C peptide do not, indicating
functional diversity within the ins family.
[Key Words: Insulin signaling; Caenorhabditis elegans; dauer; life span; C-peptide; DAF-2]
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