Research article

The Drosophila Forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling

Martin A Jünger¹, Felix Rintelen^1,2, Hugo Stocker¹, Jonathan D Wasserman^3,4, Mátyás Végh^5,6, Thomas Radimerski⁷, Michael E Greenberg³ and Ernst Hafen¹

¹Zoologisches Institut, Universität Zürich, Winterthurerstr. 190, CH-8057 Zürich, Switzerland

²Current address: Serono Pharmaceutical Research Institute, Serono International S.A. 14, Chemin des Aulx, CH-1228, Plans-les-Ouates, Geneva, Switzerland

³Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA

⁴Current address: Harvard-Massachusetts Institute of Technology, Division of Health Sciences and Technology, Cambridge, MA 02139, USA

⁵lnstitut für Molekularbiologie, Universität Zürich, Winterthurerstr. 190, CH-8057 Zürich, Switzerland

⁶Current address: The Genetics Company, Inc., Wagistr. 27, CH-8952 Schlieren, Switzerland

⁷Friedrich-Miescher-Institut, Novartis Research Foundation, Maulbeerstr. 66, CH-4058 Basel, Switzerland

author email corresponding author email

Journal of Biology 2003, 2:20doi:10.1186/1475-4924-2-20

Published:	7 August 2003

Abstract

Background

Forkhead transcription factors belonging to the FOXO subfamily are negatively regulated by protein kinase B (PKB) in response to signaling by insulin and insulin-like growth factor in Caenorhabditis elegans and mammals. In Drosophila, the insulin-signaling pathway regulates the size of cells, organs, and the entire body in response to nutrient availability, by controlling both cell size and cell number. In this study, we present a genetic characterization of dFOXO, the only Drosophila FOXO ortholog.

Results

Ectopic expression of dFOXO and human FOXO3a induced organ-size reduction and cell death in a manner dependent on phosphoinositide (PI) 3-kinase and nutrient levels. Surprisingly, flies homozygous for dFOXO null alleles are viable and of normal size. They are, however, more sensitive to oxidative stress. Furthermore, dFOXO function is required for growth inhibition associated with reduced insulin signaling. Loss of dFOXO suppresses the reduction in cell number but not the cell-size reduction elicited by mutations in the insulin-signaling pathway. By microarray analysis and subsequent genetic validation, we have identified d4E-BP, which encodes a translation inhibitor, as a relevant dFOXO target gene.

Conclusion

Our results show that dFOXO is a crucial mediator of insulin signaling in Drosophila, mediating the reduction in cell number in insulin-signaling mutants. We propose that in response to cellular stresses, such as nutrient deprivation or increased levels of reactive oxygen species, dFOXO is activated and inhibits growth through the action of target genes such as d4E-BP.