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Published on: June 30, 2011
The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced
Martin A Jünger1, Felix Rintelen, Hugo Stocker
1Zoologisches Institut, Universität Zürich, Winterthurerstr, 190, CH-8057 Zürich, Switzerland.
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.
Insights
Drosophila FOXO (dFOXO) is vital for insulin signaling, mediating growth reduction and regulating cell number. Loss of dFOXO increases sensitivity to oxidative stress and impacts nutrient availability responses.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Forkhead box O (FOXO) transcription factors are key regulators in insulin signaling pathways across species.
- In Drosophila, the insulin signaling pathway controls organismal growth in response to nutrient availability.
- dFOXO is the sole Drosophila ortholog of the FOXO subfamily.
Purpose of the Study:
- To genetically characterize the function of dFOXO in Drosophila.
- To understand dFOXO's role in insulin signaling and growth regulation.
- To identify dFOXO target genes.
Main Methods:
- Genetic characterization of dFOXO null alleles.
- Ectopic expression studies of dFOXO and human FOXO3a.
- Microarray analysis to identify target genes.
- Genetic validation of identified target genes.
Main Results:
- Ectopic dFOXO expression reduced organ size and induced cell death, dependent on PI3-kinase and nutrients.
- dFOXO null mutant flies were viable and normal in size but sensitive to oxidative stress.
- dFOXO is required for growth inhibition in insulin signaling mutants, affecting cell number but not cell size.
- d4E-BP, a translation inhibitor, was identified as a dFOXO target gene.
Conclusions:
- dFOXO is a critical mediator of insulin signaling in Drosophila, controlling cell number reduction.
- dFOXO activation, triggered by cellular stresses like nutrient deprivation or oxidative stress, inhibits growth via target genes such as d4E-BP.
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