title: Molecular evolution and functional characterization of Drosophila insulin-like peptides.
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.
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, London, United Kingdom.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Grönke
authors.forename: David-Francis
authors.initials: DF
authors.lastname: Clarke
authors.forename: Susan
authors.initials: S
authors.lastname: Broughton
authors.forename: T Daniel
authors.initials: TD
authors.lastname: Andrews
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004032:Diet; D004330:Drosophila / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000382:microbiology; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D004351:Drug Resistance / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D019143:Evolution, Molecular; D005298:Fertility / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D056426:Genetic Loci / Q000235:genetics; D008136:Longevity / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D010063:Ovum / Q000166:cytology / Q000187:drug effects; D010802:Phylogeny; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics; D016019:Survival Analysis; D013997:Time Factors; D020577:Wolbachia / Q000378:metabolism; D015262:Xenobiotics / Q000494:pharmacology
chemical_list: D029721:Drosophila Proteins; D015262:Xenobiotics