Abstract
Multicellular animals match costly activities, such as growth and reproduction, to the environment through nutrient-sensing pathways. The insulin/IGF signaling (IIS) pathway plays key roles in growth, metabolism, stress resistance, reproduction, and longevity in diverse organisms including mammals. Invertebrate genomes often contain multiple genes encoding insulin-like ligands, including seven Drosophila insulin-like peptides (DILPs). We investigated the evolution, diversification, redundancy, and functions of the DILPs, combining evolutionary analysis, based on the completed genome sequences of 12 Drosophila species, and functional analysis, based on newly-generated knock-out mutations for all 7 dilp genes in D. melanogaster. Diversification of the 7 DILPs preceded diversification of Drosophila species, with stable gene diversification and family membership, suggesting stabilising selection for gene function. Gene knock-outs demonstrated both synergy and compensation of expression between different DILPs, notably with DILP3 required for normal expression of DILPs 2 and 5 in brain neurosecretory cells and expression of DILP6 in the fat body compensating for loss of brain DILPs. Loss of DILP2 increased lifespan and loss of DILP6 reduced growth, while loss of DILP7 did not affect fertility, contrary to its proposed role as a Drosophila relaxin. Importantly, loss of DILPs produced in the brain greatly extended lifespan but only in the presence of the endosymbiontic bacterium Wolbachia, demonstrating a specific interaction between IIS and Wolbachia in lifespan regulation. Furthermore, loss of brain DILPs blocked the responses of lifespan and fecundity to dietary restriction (DR) and the DR response of these mutants suggests that IIS extends lifespan through mechanisms that both overlap with those of DR and through additional mechanisms that are independent of those at work in DR. Evolutionary conservation has thus been accompanied by synergy, redundancy, and functional differentiation between DILPs, and these features may themselves be of evolutionary advantage.
Highlights
The ability of organisms to respond appropriately to changes in their environment is key to survival and reproductive success
Most multicellular animals contain multiple insulin/insulin-like growth factors (IGF) signalling (IIS) ligands, including 7 in the fruit fly Drosophila melanogaster (DILP1-7), implying that the diverse functions of IIS could in part be mediated by the functional diversification of the ligands
We show that loss of DILP2 extends lifespan and describe a novel role for DILP6 in growth control
Summary
The ability of organisms to respond appropriately to changes in their environment is key to survival and reproductive success. An essential environmental variable for all organisms is their food supply and energetically demanding processes, such as growth, metabolism and reproduction are matched to nutrition by nutrient-sensing pathways, such as the insulin/IGF signalling (IIS) and TOR pathways [1]. The IIS pathway includes both peptide ligands, which can act at a distance, and intracellular components. The ligands include insulin, the insulin-like growth factors (IGF) and relaxins. Insulin-like peptides (ILPs) have been identified across a broad range of invertebrates, including molluscs, the nematode Caenorhabditis elegans and several insect species [3]. While mammals often have up to 4 isoforms of the cellular components of IIS, they are encoded by single genes in Drosophila, including one Drosophila Insulin receptor (DInR), one insulin receptor substrate (chico) and one downstream forkhead box O transcription factor (dFOXO) [1]. The relative simplicity of the cellular IIS pathway, together with the diversification of DILPs, implies that the diverse functions of IIS could be in part mediated by functional diversification of the ligands
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
