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      Molecular Evolution and Functional Characterization of Drosophila Insulin-Like Peptides

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          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.

          Author Summary

          The insulin/IGF signalling (IIS) pathway plays key roles in growth, metabolism, reproduction, and longevity in animals as diverse as flies and mammals. Most multicellular animals contain multiple 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. Although Drosophila is a prime model organism to study IIS, knowledge about the function of individual DILPs is still very limited due to the lack of gene-specific mutants. Therefore, we generated mutants for all 7 dilp genes and systematically analyzed their phenotypes. We show that loss of DILP2 extends lifespan and describe a novel role for DILP6 in growth control. Furthermore, we show that DILPs are evolutionary conserved and can act redundantly, supporting the hypothesis that functional redundancy itself can be of evolutionary advantage. We also describe a specific interaction between IIS and the endosymbiontic bacterium Wolbachia in lifespan regulation. This finding has implications for all longevity studies using IIS mutants in flies and offers the opportunity to study IIS as a mechanism involved in host/symbiont interactions. Finally, we show that DILPs mediate the response of lifespan and fecundity to dietary restriction.

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          Most cited references42

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          Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.

          In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.
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            Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans.

            Many conditions that shift cells from states of nutrient utilization and growth to states of cell maintenance extend lifespan. We have carried out a systematic lifespan analysis of conditions that inhibit protein synthesis. We find that reducing the levels of ribosomal proteins, ribosomal-protein S6 kinase or translation-initiation factors increases the lifespan of Caenorhabditis elegans. These perturbations, as well as inhibition of the nutrient sensor target of rapamycin (TOR), which is known to increase lifespan, all increase thermal-stress resistance. Thus inhibiting translation may extend lifespan by shifting cells to physiological states that favor maintenance and repair. Interestingly, different types of translation inhibition lead to one of two mutually exclusive outputs, one that increases lifespan and stress resistance through the transcription factor DAF-16/FOXO, and one that increases lifespan and stress resistance independently of DAF-16. Our findings link TOR, but not sir-2.1, to the longevity response induced by dietary restriction (DR) in C. elegans, and they suggest that neither TOR inhibition nor DR extends lifespan simply by reducing protein synthesis.
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              Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands.

              The insulin/insulin-like growth factor-like signaling pathway, present in all multicellular organisms, regulates diverse functions including growth, development, fecundity, metabolic homeostasis, and lifespan. In flies, ligands of the insulin/insulin-like growth factor-like signaling pathway, the Drosophila insulin-like peptides, regulate growth and hemolymph carbohydrate homeostasis during development and are expressed in a stage- and tissue-specific manner. Here, we show that ablation of Drosophila insulin-like peptide-producing median neurosecretory cells in the brain leads to increased fasting glucose levels in the hemolymph of adults similar to that found in diabetic mammals. They also exhibit increased storage of lipid and carbohydrate, reduced fecundity, and reduced tolerance of heat and cold. However, the ablated flies show an extension of median and maximal lifespan and increased resistance to oxidative stress and starvation.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                February 2010
                February 2010
                26 February 2010
                : 6
                : 2
                : e1000857
                Affiliations
                [1 ]Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, London, United Kingdom
                [2 ]European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom
                University of California San Francisco, United States of America
                Author notes

                Conceived and designed the experiments: SG LP. Performed the experiments: SG DFC SB. Analyzed the data: SG DFC TDA. Contributed reagents/materials/analysis tools: SB. Wrote the paper: SG LP.

                Article
                09-PLGE-RA-1793R2
                10.1371/journal.pgen.1000857
                2829060
                20195512
                dd8165b1-eab8-41ca-b0c1-6f4d71652ca8
                Grönke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 12 October 2009
                : 25 January 2010
                Page count
                Pages: 18
                Categories
                Research Article
                Developmental Biology/Aging
                Diabetes and Endocrinology

                Genetics
                Genetics

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