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Published on: September 13, 2017
Expression of Drosophila FOXO regulates growth and can phenocopy starvation
Jamie M Kramer1, Jason T Davidge, Joseph M Lockyer
1Department of Biology, Memorial University of Newfoundland, St, John's, Newfoundland, (A1B 3X9), Canada. x04jmk@mun.ca
Background:
Components of the insulin signaling pathway are important regulators of growth. The FOXO (forkhead box, sub-group "O") transcription factors regulate cellular processes under conditions of low levels of insulin signaling. Studies in mammalian cell culture show that activation of FOXO transcription factors causes cell death or cell cycle arrest. The Caenorhabditis elegans homologue of FOXO, Daf-16, is required for the formation of dauer larvae in response to nutritional stress. In addition, FOXO factors have been implicated in stress resistance and longevity.
Results:
We have identified the Drosophila melanogaster homologue of FOXO (dFOXO), which is conserved in amino acid sequence compared with the mammalian FOXO homologues and Daf-16. Expression of dFOXO during early larval development causes inhibition of larval growth and alterations in feeding behavior. Inhibition of larval growth is reversible upon discontinuation of dFOXO expression. Expression of dFOXO during the third larval instar or at low levels during development leads to the generation of adults that are reduced in size. Analysis of the wings and eyes of these small flies indicates that the reduction in size is due to decreases in cell size and cell number. Overexpression of dFOXO in the developing eye leads to a characteristic phenotype with reductions in cell size and cell number. This phenotype can be rescued by co-expression of upstream insulin signaling components, dPI3K and dAkt, however, this rescue is not seen when FOXO is mutated to a constitutively active form.
Conclusions:
dFOXO is conserved in both sequence and regulatory mechanisms when compared with other FOXO homologues. The establishment of Drosophila as a model for the study of FOXO transcription factors should prove beneficial to determining the biological role of these signaling molecules. The alterations in larval development seen upon overexpression of dFOXO closely mimic the phenotypic effects of starvation, suggesting a role for dFOXO in the response to nutritional adversity. This work has implications in the understanding of cancer and insulin related disorders, such as diabetes and obesity.
Insights
The Drosophila FOXO homolog (dFOXO) regulates larval growth and cell size, mimicking starvation effects. This discovery offers insights into insulin signaling, cancer, and metabolic disorders like diabetes.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- FOXO transcription factors regulate cellular processes, including growth, cell cycle arrest, and stress resistance.
- FOXO homologues are conserved across species, playing roles in development and longevity.
- Insulin signaling pathway components are crucial regulators of growth.
Purpose of the Study:
- To identify and characterize the Drosophila melanogaster homolog of FOXO (dFOXO).
- To investigate the role of dFOXO in larval development and cellular processes.
- To explore the conservation and regulatory mechanisms of FOXO transcription factors.
Main Methods:
- Identification and sequence comparison of dFOXO with mammalian FOXO and C. elegans Daf-16.
- Expression of dFOXO in Drosophila melanogaster during different larval stages.
- Analysis of larval growth, feeding behavior, adult size, cell size, and cell number.
- Rescue experiments using upstream insulin signaling components (dPI3K, dAkt) and mutated dFOXO.
Main Results:
- dFOXO expression inhibits larval growth and alters feeding behavior, effects reversible upon discontinuation.
- Overexpression of dFOXO leads to smaller adult flies due to reduced cell size and number.
- dFOXO overexpression in the eye results in a characteristic phenotype of reduced cell size and number.
- Co-expression of dPI3K and dAkt rescues the dFOXO phenotype, except when FOXO is constitutively active.
Conclusions:
- dFOXO is evolutionarily conserved in sequence and regulatory mechanisms with other FOXO homologues.
- Drosophila serves as a valuable model for studying FOXO transcription factors and their biological roles.
- dFOXO plays a role in nutritional adversity response, mimicking starvation phenotypes.
- Findings have implications for understanding cancer and insulin-related disorders like diabetes and obesity.
