In C. elegans, the nuclear hormone receptor DAF-12 plays a central role in regulating developmental progression from larva to adult. Two steroid hormones D4 and D7 -dafachronic acids have been predicted to function as ligands of DAF-12, promoting reproductive development and suppressing entry into larval diapause (dauer)1.
Previous investigations1,2,3 predominantly based on indirect feeding experiments and phenotypic based proposed a putative biosynthetic pathway for D4 and D7 -dafachronic acids involving a cytochrome P450, DAF-9; a Rieske oxygenase, DAF-36 and a hydroxysterol dehydrogenase, HSD-1. Using NMR based comparative metabolomics, we show that the biosynthetic pathway for DAF-12 ligands requires substantial revision. For example, comparison of the metabolome of hsd-1
mutants with that of hormone deficient daf-9
mutant worms revealed the presence of a novel endogenous DAF-12 ligand that is absent in wild-type worms. In contrast, hsd-1
mutants lacked a major wild-type ligand proposed to be upregulated in hsd-1
. In addition we report changes in dafachronic acid biosynthesis in several other mutant strains, including daf-36
Separate ligand biosynthetic pathways for DAF-12 leading to structurally different ligands may represent a mechanism for controlling DAF-12 function4. The identification of new components and the association of the known compounds to specific mutant backgrounds will provide a better understanding of the convergence of signals from the upstream dauer network: Guanylyl Cyclase, TGF-b and insulin/IGF-1 pathways on to the central regulator DAF-12.
1. Motola DL, Cummins CL, Rottiers V, Sharma KK, Li T, Li Y, Suino-Powell K, Xu HE, Auchus RJ, Antebi A, Mangelsdorf DJ (2006). Cell 124, 1209.
2. Rottiers, V, Motola, DL, Gerisch, B, Cummins, CL, Nishiwaki, K, Mangelsdorf, DJ, and Antebi, A (2006). Dev. Cell.10, 473.
3. Patel DS, Fang LL, Svy DK, Ruvkun G, Li W. (2008). Development. 135, 2239.
4. Dumas KJ, Guo C, Wang X, Burkhart KB, Adams EJ, Alam H, Hu PJ. (2010). Dev Biol. 340, 605.