Identification of ligands for DAF-12 that govern dauer formation and reproduction in C. elegans.
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.
Motola
Daniel L
DL
Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Cummins
Carolyn L
CL
Rottiers
Veerle
V
Sharma
Kamalesh K
KK
Li
Tingting
T
Li
Yong
Y
Suino-Powell
Kelly
K
Xu
H Eric
HE
Auchus
Richard J
RJ
Antebi
Adam
A
Mangelsdorf
David J
DJ
D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000819:agonists* / Q000187:drug effects / Q000378:metabolism*; D002783:Cholestenones / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007664:Ketosteroids / Q000494:pharmacology*; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000187:drug effects / Q000378:metabolism*; D012098:Reproduction
D029742:Caenorhabditis elegans Proteins; D002783:Cholestenones; C410905:DAF-12 protein, C elegans; D007664:Ketosteroids; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; C000475:cholest-4-en-3-one; D003577:Cytochrome P-450 Enzyme System; C486228:DAF-9 protein, C elegans