An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology.

TitleAn insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology.
Publication TypeJournal Article
Year of Publication2014
Authorsde Abreu DAndrea Fer, Caballero A, Fardel P, Stroustrup N, Chen Z, Lee K, Keyes WD, Nash ZM, López-Moyado IF, Vaggi F, Cornils A, Regenass M, Neagu A, Ostojic I, Liu C, Cho Y, Sifoglu D, Shen Y, Fontana W, Lu H, Csikasz-Nagy A, Murphy CT, Antebi A, Blanc E, Apfeld J, Zhang Y, Alcedo J, Ch'ng Q
JournalPLoS Genet
Volume10
Issue3
Paginatione1004225
Date Published2014 Mar
ISSN1553-7404
KeywordsAnimals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Gene Regulatory Networks, Insulin, Longevity, Phenotype, Receptor, Insulin, Signal Transduction, Somatomedins
Abstract

Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. Our systematic studies identify an ILP-based combinatorial code for these phenotypes characterized by substantial functional specificity and diversity rather than global redundancy. Notably, we show that ILPs regulate each other transcriptionally, uncovering an ILP-to-ILP regulatory network that underlies the combinatorial phenotypic coding by the ILP family. Extensive analyses of genetic interactions among ILPs reveal how their signals are integrated. A combined analysis of these functional and regulatory ILP interactions identifies local genetic circuits that act in parallel and interact by crosstalk, feedback and compensation. This organization provides emergent mechanisms for phenotypic specificity and graded regulation for the combinatorial phenotypic coding we observe. Our findings also provide insights into how large hormonal networks regulate diverse traits.

DOI10.1371/journal.pgen.1004225
Alternate JournalPLoS Genet.
PubMed ID24675767
PubMed Central IDPMC3967928
Grant ListR01 DC009852 / DC / NIDCD NIH HHS / United States
R01GM088333 / GM / NIGMS NIH HHS / United States
G0901899 / / Medical Research Council / United Kingdom
P40 OD010440 / OD / NIH HHS / United States
R03 AG032481 / AG / NIA NIH HHS / United States
DP2 OD004402-01 / OD / NIH HHS / United States
R21EB012803 / EB / NIBIB NIH HHS / United States
R01AG035317 / AG / NIA NIH HHS / United States
R01 AG034994 / AG / NIA NIH HHS / United States