Drosophila FoxO Regulates Organism Size and Stress Resistance through an Adenylate Cyclase

Abstract

Forkhead box class O (FoxO) transcription factors are a family of conserved proteins that regulate the cellular responses to various stimuli, such as energy deprivation, stress, and developmental cues. FoxO proteins are important mediators of the insulin signaling pathway, adjusting growth and metabolism to nutrient availability. Insulin signaling acts together with the glucagon-stimulated cAMP signaling pathway to orchestrate the organism response to various nutritional conditions. In this study, we demonstrate that Drosophila melanogaster FoxO (dFoxO) regulates cAMP signaling by directly inducing the expression of an adenylate cyclase gene, ac76e. Interestingly, ac76e is expressed in a highly restricted pattern throughout fly development, limited to the corpus allatum (CA), gastric cecum, and malpighian tubules. dFoxO activation of AC76E in the CA increases starvation resistance and limits growth. Our results unravel a new role for dFoxO, integrating cAMP and insulin signaling to adapt organism growth to the existing nutritional conditions.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We thank Terhi Vihervaara for her help in band shifts and ChIP experiments. We thank Osamu Shimmi and Ville Hietakangas for comments on the manuscript. We are grateful to Jean-René Martin for providing us with the DI-11 fly stock.

This work was supported by the Helsinki Graduate School in Biotechnology and Molecular Biology and the Finnish Cultural Foundation (J.M.) and by grants from the Finnish Diabetes Association, Novo Nordisk, and the Juselius Foundation (to O.P.).