Identification of Ligands for DAF-12 that Govern Dauer Formation and Reproduction in C. elegans

Daniel L. Motola, Carolyn L. Cummins, Veerle Rottiers, Kamalesh K. Sharma, Tingting Li, Yong Li, Kelly Suino-Powell, H. Eric Xu, Richard J. Auchus, Adam Antebi, David J. Mangelsdorf

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311 Scopus citations

Abstract

In response to environmental and dietary cues, the C. elegans orphan nuclear receptor, DAF-12, regulates dauer diapause, reproductive development, fat metabolism, and life span. Despite strong evidence for hormonal control, the identification of the DAF-12 ligand has remained elusive. In this work, we identified two distinct 3-keto-cholestenoic acid metabolites of DAF-9, a cytochrome P450 involved in hormone production, that function as ligands for DAF-12. At nanomolar concentrations, these steroidal ligands (called dafachronic acids) bind and transactivate DAF-12 and rescue the hormone deficiency of daf-9 mutants. Interestingly, DAF-9 has a biochemical activity similar to mammalian CYP27A1 catalyzing addition of a terminal acid to the side chain of sterol metabolites. Together, these results define the first steroid hormones in nematodes as ligands for an invertebrate orphan nuclear receptor and demonstrate that steroidal regulation of reproduction, from biology to molecular mechanism, is conserved from worms to humans.

Original languageEnglish (US)
Pages (from-to)1209-1223
Number of pages15
JournalCell
Volume124
Issue number6
DOIs
StatePublished - Mar 24 2006

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Motola, D. L., Cummins, C. L., Rottiers, V., Sharma, K. K., Li, T., Li, Y., Suino-Powell, K., Xu, H. E., Auchus, R. J., Antebi, A., & Mangelsdorf, D. J. (2006). Identification of Ligands for DAF-12 that Govern Dauer Formation and Reproduction in C. elegans. Cell, 124(6), 1209-1223. https://doi.org/10.1016/j.cell.2006.01.037