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In Vivo Imaging of Dauer-specific Neuronal Remodeling in C. elegans
Published on: September 4, 2014
Caenorhabditis elegans EAK-3 inhibits dauer arrest via nonautonomous regulation of nuclear DAF-16/FoxO activity
Yanmei Zhang1, Jinling Xu, Cristina Puscau
1Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Abstract:
Insulin regulates development, metabolism, and lifespan via a conserved PI3K/Akt pathway that promotes cytoplasmic sequestration of FoxO transcription factors. The regulation of nuclear FoxO is poorly understood. In the nematode Caenorhabditis elegans, insulin-like signaling functions in larvae to inhibit dauer arrest and acts during adulthood to regulate lifespan. In a screen for genes that modulate C. elegans insulin-like signaling, we identified eak-3, which encodes a novel protein that is specifically expressed in the two endocrine XXX cells. The dauer arrest phenotype of eak-3 mutants is fully suppressed by mutations in daf-16/FoxO, which encodes the major target of C. elegans insulin-like signaling, and daf-12, which encodes a nuclear receptor regulated by steroid hormones known as dafachronic acids. eak-3 mutation does not affect DAF-16/FoxO subcellular localization but enhances expression of the direct DAF-16/FoxO target sod-3 in a daf-16/FoxO- and daf-12-dependent manner. eak-3 mutants have normal lifespans, suggesting that EAK-3 decouples insulin-like regulation of development and longevity. We propose that EAK-3 activity in the XXX cells promotes the synthesis and/or secretion of a hormone that acts in parallel to AKT-1 to inhibit the expression of DAF-16/FoxO target genes. Similar hormonal pathways may regulate FoxO target gene expression in mammals.
Insights
A novel gene, eak-3, in C. elegans insulin signaling decouples development from lifespan regulation. EAK-3 acts in endocrine cells to control FoxO target gene expression, impacting dauer arrest but not longevity.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Insulin signaling, mediated by the PI3K/Akt pathway, controls development, metabolism, and lifespan by regulating FoxO transcription factors.
- The precise mechanisms governing nuclear FoxO regulation remain incompletely understood.
- In Caenorhabditis elegans, insulin signaling influences larval dauer arrest and adult lifespan.
Purpose of the Study:
- To identify novel genes modulating insulin-like signaling in C. elegans.
- To elucidate the role of the identified gene, eak-3, in the regulation of insulin signaling pathways.
- To investigate how EAK-3 influences the developmental and longevity effects of insulin signaling.
Main Methods:
- Genetic screens in C. elegans to identify modulators of insulin signaling.
- Analysis of mutant phenotypes, including dauer arrest and lifespan.
- Examination of gene expression, specifically for DAF-16/FoxO target genes like sod-3.
- Assessment of DAF-16/FoxO subcellular localization.
Main Results:
- The gene eak-3 was identified as a novel modulator of C. elegans insulin-like signaling, specifically expressed in endocrine XXX cells.
- Mutations in eak-3 suppressed dauer arrest phenotypes in conjunction with daf-16/FoxO and daf-12 mutations.
- eak-3 mutation did not alter DAF-16/FoxO localization but enhanced sod-3 expression in a daf-16/FoxO- and daf-12-dependent manner.
- eak-3 mutants exhibited normal lifespans, indicating a decoupling of developmental and longevity regulation.
Conclusions:
- EAK-3 plays a critical role in regulating C. elegans development by influencing DAF-16/FoxO target gene expression.
- EAK-3 appears to decouple the insulin-regulated pathways controlling development and lifespan.
- A proposed model suggests EAK-3 acts in endocrine XXX cells to promote a hormone that parallels AKT-1 signaling to inhibit DAF-16/FoxO target gene expression, with potential implications for mammalian FoxO regulation.
