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.

Sebastian Grönke

David-Francis Clarke

Susan Broughton

T. Daniel Andrews

Linda Partridge

PLoS Genetics

PLOS GENETICS 由一个国际编辑委员会管理，该委员会由主编 GREG BARSH（哈德逊阿尔法生物技术研究所和斯坦福大学医学院）和 GREG COPENHAVER（北卡罗来纳大学教堂山分校）领导。发表的文章PLOS GENETICS 中的 IN 存档在 PUBMED CENTRAL 中并在 PUBMED 中引用。

PLOS GENETICS is managed by an international editorial board led by editors-in-chief GREG BARSH (Hudson Alpha Institute for Biotechnology and Stanford University School of Medicine) and GREG COPENHAVER (University of North Carolina at Chapel Hill). Articles published in PLOS GENETICS are archived in PUBMED CENTRAL and cited in PUBMED.

《PLoS Genetics》由国际编辑委员会管理，主编为GREG BARSH（哈德逊阿尔法生物技术研究所和斯坦福大学医学院）和GREG COPENHAVER（北卡罗来纳大学教堂山分校）。该期刊发表的文章会在PUBMED CENTRAL进行存档，并在PUBMED中引用。

PLoS Genet

Molecular Evolution and Functional Characterization of Drosophila Insulin-Like Peptides

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.

Category	Quartile
生物学	2
生物学, 遗传学	2

Molecular Evolution and Functional Characterization of Drosophila Insulin-Like Peptides

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