Molecular Evolution and Functional Characterization of Drosophila Insulin-Like Peptides

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Molecular Evolution and Functional Characterization of Drosophila Insulin-Like Peptides

Gronke, S; Clarke, DF; Broughton, S; Andrews, TD; Partridge, L; (2010) Molecular Evolution and Functional Characterization of Drosophila Insulin-Like Peptides. PLOS GENET , 6 (2) , Article e1000857. 10.1371/journal.pgen.1000857. Green open access

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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.

Type:	Article
Title:	Molecular Evolution and Functional Characterization of Drosophila Insulin-Like Peptides
Open access status:	An open access version is available from UCL Discovery
DOI:	10.1371/journal.pgen.1000857
Publisher version:	http://dx.doi.org/10.1371/journal.pgen.1000857
Language:	English
Additional information:	© 2010 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. Funding: This work was supported by the Leverhulme Trust - Evolutionary Genetics of Human Nutrition Grant, http://www.leverhulme.org.uk/; the Wellcome Trust - Functional Genomic Analysis of Ageing Grant, http://www.wellcome.ac.uk/, and by the Max Planck Society, http://www.mpg.de/english/portal/index.html. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords:	LIFE-SPAN EXTENSION, DIETARY RESTRICTION, GENETIC REDUNDANCY, CAENORHABDITIS-ELEGANS, GROWTH, EXPRESSION, CELLS, FLIES, RECEPTOR, SYSTEM
UCL classification:	UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI:	https://discovery.ucl.ac.uk/id/eprint/134780