Daniel L. Motola1, Carolyn L. Cummins1, Veerle Rottiers3, Kamalesh K.Sharma2, Tingting Li1, Yong Li4, Kelly Suino-Powell4, H. Eric Xu4, Richard J. Auchus2, Adam Antebi3, and David J. Mangelsdorf1. The C. elegans orphan nuclear receptor, DAF-12, lies at the convergence of signaling pathways that couple environmental cues such as food availability, temperature, and population density to the choice between reproductive development or the formation of the long-lived, stress-resistant dauer larva [1]. Genetic dissection of these signaling pathways suggests that in favorable environments the choice of reproduction requires the production of a ligand for DAF-12 produced by the cytochrome
p450, DAF-9. The DAF-12 ligand likely derives from dietary cholesterol as C. elegans requires cholesterol for normal growth and its deprivation in wild-type worms phenocopies the constitutive dauer formation (Daf-c) and gonadal migration (Mig) phenotypes associated with loss of
daf-9 or point mutations in the ligand binding domain of DAF-12 [2]. Despite these findings 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 that function as ligands for DAF-12. 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. Finally, this work also raises the possibility of targeting nuclear receptors in parasitic nematodes as a strategy for controlling their growth.. References:. 1.. Riddle, D.L. and Albert, P.S., Genetic and environmental regulation of dauer larva development., in In C. elegans II D.L. Riddle, et al., Editors. 1997, Cold Spring Harbor Laboratory Press: Colds Spring Harbor.. 2.. Gerisch, B., Weitzel, C., Kober-Eisermann, C., Rottiers, V., and Antebi, A., A hormonal signaling pathway influencing C. elegans metabolism, reproductive development, and life span. Dev Cell, 2001. 1(6): p. 841-51..