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

  1. Sarah B. Pierce1,4,
  2. Michael Costa2,4,
  3. Robert Wisotzkey3,5,
  4. Sharmila Devadhar2,
  5. Sheila A. Homburger2,
  6. Andrew R. Buchman2,
  7. Kimberly C. Ferguson2,
  8. Jonathan Heller2,
  9. Darren M. Platt2,
  10. Amy A. Pasquinelli1,
  11. Leo X. Liu3,6,
  12. Stephen K. Doberstein2, and
  13. Gary Ruvkun1,7
  1. 1Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA; 2Exelixis Pharmaceuticals, Inc., South San Francisco, California 94080, USA; 3Axys Pharmaceuticals, NemaPharm Group, South San Francisco, California 94080, USA

Abstract

The activity of the DAF-2 insulin-like receptor is required forCaenorhabditis 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 weakdaf-2 mutants, suggesting that INS-1 and human insulin antagonize DAF-2 insulin-like signaling. A deletion of theins-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.

Keywords

Footnotes

  • 4 These authors contributed equally to this work.

  • Present addresses: 5Deltagen, Menlo Park, CA 94025, USA; 6Cambria Biosciences LLC, Bedford, MA 01730, USA.

  • 7 Corresponding author.

  • E-MAIL ruvkun{at}frodo.mgh.harvard.edu; FAX (617) 726-6893.

  • Article and publication are at www.genesdev.org/cgi/doi/10.1101/gad.867301.

    • Received November 17, 2000.
    • Accepted January 19, 2001.
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