Expressionof Drosophila FOXO regulates growth and can phenocopy starvation

Abstract

BackgroundComponents 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 Caenorhabiditis 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.ResultsWe 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.ConclusionsdFOXO 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.

Crossing the Worm-Brain Barrier by Using <b><i>Caenorhabditis elegans</i></b> to Explore Fundamentals of Human Psychiatric Illness

“…Overexpression of forkhead box O (FOXO) genes in Drosophila produces an anorexic phenotype characterized by apparent ambivalence toward food, decreased food consumption, reduced foraging, and slower reproductive maturation [48]. A similar decrease in foraging has been observed when FOXO (DAF-16) activity is increased in C. elegans [49].…”

Prowashonupana barley dietary fibre reduces body fat and increases insulin sensitivity in Caenorhabditis elegans model

“…C. elegans dauer formation ( daf ) gene, daf-2 , is a homolog of the insulin and insulin-like growth factor (IGF) receptor in humans and is the only gene encoding the insulin/IGF-1 like receptor in C. elegans (Zheng & Greenway, 2012). Decreased daf-2 signalling increases C. elegans lifespan (Koga, Take-uchi, Tameishi, & Ohshima, 1999; Kramer, Davidge, Lockyer, & Staveley, 2003) which fully depends upon daf-16 (Patel et al, 2008), since daf-16 null mutations completely suppress the extension of lifespan by daf-2 (e1370)III null mutant (Burks et al, 2000; Hertweck, Gobel, & Baumeister, 2004; Hunt et al, 2011; Tissenbaum & Ruvkun, 1998; Yu et al, 2010). Hyperglycaemia (2% glucose) causes insulin resistance in N2 and daf-2(e1370)III null mutants, and reduces pharyngeal movement, a surrogate marker directly related to lifespan (Abate & Blackwell, 2009).…”

The Temporal Requirements for Insulin Signaling During Development in Drosophila

“…Insulin signaling may therefore continue to influence size after pupariation. Details of the temporal requirements for insulin signaling are unknown in Drosophila, but a recent study on the Drosophila forkhead transcription factor (dFOXO) suggests that they vary during development [14]. Unphosphorylated dFOXO negatively regulates growth, but activation of the insulin receptor signaling pathway induces dFOXO phosphorylation, excluding it from the nucleus and inhibiting its activity [15,16].…”

“…Unphosphorylated dFOXO negatively regulates growth, but activation of the insulin receptor signaling pathway induces dFOXO phosphorylation, excluding it from the nucleus and inhibiting its activity [15,16]. Constitutive activation of dFOXO in the first and second instars causes developmental arrest, whereas dFOXO activation in the third instar causes a reduction in adult size [14]. Work on Caenorhabditis elegans also indicates that the timing requirements for insulin signaling might vary during the lifecycle.…”