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 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) isomerases (3beta-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 3beta-HSD function in the dafachronic acid biosynthetic pathway, suggesting that HSD-1 functions as a 3beta-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.
Patel
Dhaval S
DS
Department of Biological Structure, University of Washington, Seattle, WA, USA.
Fang
Lily L
LL
Svy
Danika K
DK
Ruvkun
Gary
G
Li
Weiqing
W
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004703:Endocrine System / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007814:Larva / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D015394:Molecular Structure; D010641:Phenotype; D012098:Reproduction; D015398:Signal Transduction; D013256:Steroids / Q000096:biosynthesis* / Q000737:chemistry
D029742:Caenorhabditis elegans Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C495203:NCR-1 protein, C elegans; C495204:NCR-2 protein, C elegans; D013256:Steroids; D015096:3-Hydroxysteroid Dehydrogenases