• Open Access

Lipophilic regulator of a developmental switch in Caenorhabditis elegans

Authors

  • Matthew S. Gill,

    Corresponding author
    1. Buck Institute, 8001 Redwood Boulevard, Novato, CA 94945, USA

      Matthew S Gill, Buck Institute, 8001 Redwood Boulevard, Novato, CA 94945, USA. Tel.: +1 415 2092073; fax: +1 415 2092232; e-mail: mgill@buckinstitute.org
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  • Jason M. Held,

    1. Buck Institute, 8001 Redwood Boulevard, Novato, CA 94945, USA
    2. Department of Biopharmaceutical Sciences,
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  • Alfred L. Fisher,

    1. Buck Institute, 8001 Redwood Boulevard, Novato, CA 94945, USA
    2. Department of Medicine, Division of Geriatrics, and
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  • Bradford W. Gibson,

    1. Buck Institute, 8001 Redwood Boulevard, Novato, CA 94945, USA
    2. Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94121, USA
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  • Gordon J. Lithgow

    1. Buck Institute, 8001 Redwood Boulevard, Novato, CA 94945, USA
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Matthew S Gill, Buck Institute, 8001 Redwood Boulevard, Novato, CA 94945, USA. Tel.: +1 415 2092073; fax: +1 415 2092232; e-mail: mgill@buckinstitute.org

Abstract

In Caenorhabditis elegans, the decision to develop into a reproductive adult or arrest as a dauer larva is influenced by multiple pathways including insulin-like and transforming growth factor β (TGFβ)-like signalling pathways. It has been proposed that lipophilic hormones act downstream of these pathways to regulate dauer formation. One likely target for such a hormone is DAF-12, an orphan nuclear hormone receptor that mediates these developmental decisions and also influences adult lifespan. In order to find lipophilic hormones we have generated lipophilic extracts from mass cultures of C. elegans and shown that they rescue the dauer constitutive phenotype of class 1 daf-2 insulin signalling mutants and the TGFβ signalling mutant daf-7. These extracts are also able to rescue the lethal dauer phenotype of daf-9 mutants, which lack a P450 steroid hydroxylase thought to be involved in the synthesis of the DAF-12 ligand; extracts, however, have no effect on a DAF-12 ligand binding domain mutant that is predicted to be ligand insensitive. The production of this hormone appears to be DAF-9 dependent as extracts from a daf-9;daf-12 double mutant do not exhibit this activity. Preliminary fractionation of the lipophilic extracts shows that the activity is hydrophobic with some polar properties, consistent with a small lipophilic hormone. We propose that the dauer rescuing activity is a hormone synthesized by DAF-9 that acts through DAF-12.

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