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First published online 21 May 2008
doi: 10.1242/dev.016972

Development 135, 2239-2249 (2008)
Published by The Company of Biologists 2008
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Genetic identification of HSD-1, a conserved steroidogenic enzyme that directs larval development in Caenorhabditis elegans

Dhaval S. Patel1, Lily L. Fang1, Danika K. Svy1, Gary Ruvkun2 and Weiqing Li1,*

1 Department of Biological Structure, University of Washington, Seattle, WA, USA.
2 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.

* Author for correspondence (e-mail: weiqing{at}u.washington.edu)

Accepted 1 May 2008

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 3β-hydroxysteroid dehydrogenase/{Delta}5-{Delta}4 isomerases (3β-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 3β-HSD function in the dafachronic acid biosynthetic pathway, suggesting that HSD-1 functions as a 3β-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.

Key words: 3β-HSD, Steroid hormone, Dauer, Insulin/IGF-1, NPC1, Niemann-Pick C


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Worming into steroid and insulin signal intersection

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