In C. elegans, steroid hormones, such as <font face=symbol>D</font>4 and <font face=symbol>D</font>7 dafachronic acids, have been shown to prevent dauer arrest. However, C. elegans cannot synthesize these hormones de novo, instead it modifies sterol precursors, such as cholesterol, which it acquires from its environment. Two intracellular cholesterol transporters, NCR-1 and -2, have been shown to function redundantly in preventing dauer arrest. We performed an enhancer screen for transient dauer arrest in an
ncr-1 background and identified the
mg433 allele. We established that
mg433 is an early stop mutation in a predicted 3-<font face=symbol>b</font> hydroxysteroid dehydrogenase gene, which we have termed
hsd-1. The HSD-1 protein belongs to a conserved family of steroidogenic enzymes that function in the ER. The expression of
hsd-1 is exclusive to the XXX cells, overlapping with the broader expression of
ncr-1.
hsd-1(
mg433) alone has a wild-type growth phenotype, but it is hypersensitive to dauer pheromone. A two-branch pathway is predicted to generate <font face=symbol>D</font>4 and <font face=symbol>D</font>7 dafachronic acids from cholesterol. If
hsd-1 functions like mammalian 3-<font face=symbol>b</font> HSDs, it should act in the <font face=symbol>D</font>4-branch catalyzing a two-step reaction that first converts cholesterol to 5-cholesten-3-one and then to 4-cholesten-3-one. We found that this predicted end product substantially rescued pheromone hypersensitivity in
hsd-1(
mg433), unlike the intermediate product, confirming that
hsd-1 functions like 3-<font face=symbol>b</font> HSDs. The dauer arrest of
hsd-1;
ncr-1 double mutants also showed similar rescue. Given that either <font face=symbol>D</font>4 or <font face=symbol>D</font>7 steroids can prevent dauer arrest, we tested whether raising the level of <font face=symbol>D</font>7 signaling would compensate for the lack of
hsd-1. We found that two intermediates in the <font face=symbol>D</font>7 branch, lathosterol and lathosterone, can suppress
hsd-1 pheromone hypersensitivity and
hsd-1;
ncr-1 dauer arrest. To determine whether these sterols are trafficked through NCR-1 and -2 transporters, we tested them for suppression of
ncr-2;
ncr-1 dauer arrest. We found that all the intermediates mentioned above displayed suppression, suggesting that the role of NCR transporters may be limited to mobilizing cholesterol to the ER for the HSD-1 reaction. Intermediates that are independent of this reaction may be trafficked to target organelles via other mechanisms. Given that 95% of Niemann-Pick type C neuro-degeneration results from a defective NPC1 gene, the human ortholog of NCR-1 and -2, our findings suggest that sterols bypassing the need for NPC1 may provide therapy for the disease.