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

Developmental biology

Kathleen J.Dumas¹ 

关键词: C. elegans;    Dauer;    Lifespan;    Aging;    Insulin signaling;    Steroid hormones;    Nuclear receptors;    Dafachronic acids;    Akt;    FoxO;   

DOI  :  10.1016/j.ydbio.2010.02.022

学科分类：生物科学（综合）

来源: Academic Press

【 摘 要 】

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 Δ4- and Δ7-dafachronic acid (DA) promote bypass of the dauer diapause and proper gonadal migration during larval development; in adults, DAs influence lifespan. Whether Δ4- and Δ7-DA have unique biological functions is not known. We identified the 3-β-hydroxysteroid dehydrogenase (3βHSD) family member HSD-1, which participates in Δ4-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 Δ7-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 Δ4- and Δ7-DA pathways have unique as well as overlapping biological functions in the control of development and lifespan.

【 授权许可】

CC BY