TY - JOUR
T1 - Identification of Ligands for DAF-12 that Govern Dauer Formation and Reproduction in C. elegans
AU - Motola, Daniel L.
AU - Cummins, Carolyn L.
AU - Rottiers, Veerle
AU - Sharma, Kamalesh K.
AU - Li, Tingting
AU - Li, Yong
AU - Suino-Powell, Kelly
AU - Xu, H. Eric
AU - Auchus, Richard J.
AU - Antebi, Adam
AU - Mangelsdorf, David J.
N1 - Funding Information:
We thank Jim McKay, Leon Avery, Sylvain Lebreton, Jian Chen, Joon-Cheol Kwon, Rebecca Lehotzky, and Daniel Schmidt for technical assistance; Keith Yamamoto and David Russell for plasmids; Jeffrey McDonald from the Lipid Maps Project (GM069338); and Donald Riddle and J.H. Thomas for worm strains. This work was supported by the Howard Hughes Medical Institute (D.J.M.); Robert A. Welch Foundation grants I-1275 (D.J.M.) and I-1493 (R.J.A.); National Institutes of Health grants GM07062 (D.L.M.), DK62434 and AG027498 (D.J.M. and A.A.), DK0716620 (H.E.X.), and DK59942 (R.J.A.); Jay and Betty Van Andel Foundation (H.E.X.); Department of Defense W81XWH0510043 (H.E.X.); and Glenn/AFAR Breakthroughs in Gerontology (A.A). D.J.M. is an investigator and C.L.C is an associate of the Howard Hughes Medical Institute.
PY - 2006/3/24
Y1 - 2006/3/24
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2006.01.037
DO - 10.1016/j.cell.2006.01.037
M3 - Article
C2 - 16529801
AN - SCOPUS:33646042547
SN - 0092-8674
VL - 124
SP - 1209
EP - 1223
JO - Cell
JF - Cell
IS - 6
ER -