Functional divergence of dafachronic acid pathways in the control of C. elegans development and lifespan.

Authors: Dumas KJ; Guo C; Wang X; Burkhart KB; Adams EJ; Alam H; Hu PJ

Abstract: Steroid hormone and insulin/insulin-like growth factor signaling (IIS) pathways control development and lifespan in the nematode Caenorhabditis elegans by regulating the activity of the nuclear receptor DAF-12 and the FoxO transcription factor DAF-16, respectively. The DAF-12 ligands Delta(4)- and Delta(7)-dafachronic acid (DA) promote bypass of the dauer diapause and proper gonadal migration during larval development; in adults, DAs influence lifespan. Whether Delta(4)- and Delta(7)-DA have unique biological functions is not known. We identified the 3-beta-hydroxysteroid dehydrogenase (3betaHSD) family member HSD-1, which participates in Delta(4)-DA biosynthesis, as an inhibitor of DAF-16/FoxO activity. Whereas IIS promotes the cytoplasmic sequestration of DAF-16/FoxO, HSD-1 inhibits nuclear DAF-16/FoxO activity without affecting DAF-16/FoxO subcellular localization. Thus, HSD-1 and IIS inhibit DAF-16/FoxO activity via distinct and complementary mechanisms. In adults, HSD-1 was required for full lifespan extension in IIS mutants, indicating that HSD-1 interactions with IIS are context-dependent. In contrast to the Delta(7)-DA biosynthetic enzyme DAF-36, HSD-1 is dispensable for proper gonadal migration and lifespan extension induced by germline ablation. These findings provide insights into the molecular interface between DA and IIS pathways and suggest that Delta(4)- and Delta(7)-DA pathways have unique as well as overlapping biological functions in the control of development and lifespan.

Keywords: Animals; Animals, Genetically Modified; Caenorhabditis elegans/genetics/*physiology; Cholestenes/*metabolism; *Gene Expression Regulation, Developmental; Genes, Helminth; Green Fluorescent Proteins/genetics/metabolism; Longevity/genetics/*physiology; Models, Biological; Mutation; Recombinant Fusion Proteins/metabolism; Signal Transduction/physiology; Transgenes
Journal: Developmental biology
Volume: 340
Issue: 2
Pages: 605-12
Date: Feb. 25, 2010
PMID: 20178781
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Citation:

Dumas KJ, Guo C, Wang X, Burkhart KB, Adams EJ, Alam H, Hu PJ (2010) Functional divergence of dafachronic acid pathways in the control of C. elegans development and lifespan. Developmental biology 340: 605-12.


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