Genetic identification of HSD-1, a conserved steroidogenic enzyme that directs larval development in Caenorhabditis elegans

In C. elegans, steroid hormones function in conjunction with insulin/IGF-1-like signaling in promoting reproductive development over entry into the diapausal dauer stage. The NCR-1 and -2 (NPC1-related) intracellular cholesterol transporters function redundantly in preventing dauer arrest, presumably by regulating the availability of substrates for steroid hormone synthesis. We have identified hsd-1 as a new component of this cholesterol trafficking/processing pathway, using an ncr-1 enhancer screen. HSD-1 is orthologous to 3-hydroxysteroid dehydrogenase/⁵-⁴ isomerases (3-HSDs), which are key steroidogenic enzymes in vertebrates, and is exclusively expressed in two neuron-like XXX cells that are crucial in preventing dauer arrest, suggesting that it is involved in biosynthesis of dauer-preventing steroid hormones. The hsd-1 null mutant displays defects in inhibiting dauer arrest: it forms dauers in the deletion mutant backgrounds of ncr-1 or daf-28/insulin; as a single mutant, it is hypersensitive to dauer pheromone. We found that hsd-1 defects can be rescued by feeding mutant animals with several steroid intermediates that are either downstream of or in parallel to the 3-HSD function in the dafachronic acid biosynthetic pathway, suggesting that HSD-1 functions as a 3-HSD. Interestingly, sterols that rescued hsd-1 defects also bypassed the need for the NCR-1 and/or -2 functions, suggesting that HSD-1-mediated steroid hormone production is an important functional output of the NCR transporters. Finally, we found that the HSD-1-mediated signal activates insulin/IGF-I signaling in a cell non-autonomous fashion, suggesting a novel mechanism for how these two endocrine pathways intersect in directing development.