An Insulin-to-Insulin Regulatory Network Orchestrates Phenotypic Specificity in Development and Physiology

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.

• Publication year

  2014

• Venue

  PLoS Genetics

• Publication date

  2014-03-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pgen.1004225PMID 24675767PMCID 3967928
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• 6-2013 Complex expression dynamics and robustness in C . elegans insulin networks

  2015influential reference
• Two insulin-like peptides antagonistically regulate aversive olfactory learning in C. elegans.

  2013cited by this paper
• Human diseases through the lens of network biology.

  2013cited by this paper
• The C. elegans Lifespan Machine

  2013cited by this paper
• Complex expression dynamics and robustness in C. elegans insulin networks

  2013cited by this paper
• Secreted Peptide Dilp8 Coordinates Drosophila Tissue Growth with Developmental Timing

  2012cited by this paper
• Drosophila insulin-like peptide-6 (dilp6) expression from fat body extends lifespan and represses secretion of Drosophila insulin-like peptide-2 from the brain

  2012cited by this paper
• Multi-scale structure and geographic drivers of cross-infection within marine bacteria and phages

  2012cited by this paper
• Improved Mos1-mediated transgenesis in C. elegans

  2012cited by this paper
• Physiological function, expression pattern, and transcriptional regulation of a Caenorhabditis elegans insulin-like peptide, INS-18.

  2012cited by this paper
• Imaginal Discs Secrete Insulin-Like Peptide 8 to Mediate Plasticity of Growth and Maturation

  2012cited by this paper
• Large-Scale Screening for Targeted Knockouts in the Caenorhabditis elegans Genome

  2012cited by this paper
• Beyond the connectome: How neuromodulators shape neural circuits

  2012cited by this paper
• Linkers of Cell Polarity and Cell Cycle Regulation in the Fission Yeast Protein Interaction Network

  2012cited by this paper
• Fat cells reactivate quiescent neuroblasts via TOR and glial Insulin relays in Drosophila

  2011cited by this paper
• Insulin/Insulin-Like Growth Factor Signaling Controls Non-Dauer Developmental Speed in the Nematode Caenorhabditis elegans

  2011cited by this paper
• Specific insulin-like peptides encode sensory information to regulate distinct developmental processes

  2011cited by this paper
• GPA‐9 is a novel regulator of innate immunity against Escherichia coli foods in adult Caenorhabditis elegans

  2011cited by this paper
• Statistical structure of host–phage interactions

  2011cited by this paper
• Sensitive and Precise Quantification of Insulin-Like mRNA Expression in Caenorhabditis elegans

  2011cited by this paper
• Insulin signaling promotes germline proliferation in C. elegans

  2010cited by this paper
• Molecular Evolution and Functional Characterization of Drosophila Insulin-Like Peptides

  2010cited by this paper
• TGF-β and insulin signaling regulate reproductive aging via oocyte and germline quality maintenance.

  2010cited by this paper
• Insulin-like signaling determines survival during stress via posttranscriptional mechanisms in C. elegans.

  2010cited by this paper
• Neuropeptide feedback modifies odor-evoked dynamics in C. elegans olfactory neurons

  2010cited by this paper
• Need-Based Up-Regulation of Protein Levels in Response to Deletion of Their Duplicate Genes

  2010cited by this paper
• Insulin signaling promotes germline proliferation in C. elegans

  2010cited by this paper
• A Neuromedin U Receptor Acts with the Sensory System to Modulate Food Type-Dependent Effects on C. elegans Lifespan

  2010cited by this paper
• Sensory influence on homeostasis and lifespan: molecules and circuits.

  2010cited by this paper
• Genetic redundancy: new tricks for old genes.

  2009influential reference
• A Drosophila Insulin-like Peptide Promotes Growth during Nonfeeding States

  2009cited by this paper
• TGF-ß Sma/Mab Signaling Mutations Uncouple Reproductive Aging from Somatic Aging

  2009cited by this paper
• Pervasive and Persistent Redundancy among Duplicated Genes in Yeast

  2008cited by this paper
• Exploring Network Structure, Dynamics, and Function using NetworkX

  2008cited by this paper
• Insulin-like signaling, nutrient homeostasis, and life span.

  2008cited by this paper
• Network ‘Small-World-Ness’: A Quantitative Method for Determining Canonical Network Equivalence

  2008cited by this paper
• The extensive and condition-dependent nature of epistasis among whole-genome duplicates in yeast.

  2008cited by this paper
• C. elegans dauer formation and the molecular basis of plasticity.

  2008cited by this paper
• Reduction of DILP2 in Drosophila Triages a Metabolic Phenotype from Lifespan Revealing Redundancy and Compensation among DILPs

  2008cited by this paper
• Single-copy insertion of transgenes in Caenorhabditis elegans

  2008cited by this paper
• Neuropeptidergic signaling in the nematode Caenorhabditis elegans.

  2007cited by this paper
• Travelling gradients in interacting morphogen systems.

  2007cited by this paper
• The Importance of Bottlenecks in Protein Networks: Correlation with Gene Essentiality and Expression Dynamics

  2007cited by this paper
• ASNA-1 positively regulates insulin secretion in C. elegans and mammalian cells.

  2007cited by this paper
• Network motifs: theory and experimental approaches

  2007cited by this paper
• Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans

  2007cited by this paper
• Disruption of ins-11, a Caenorhabditis elegans Insulin-Like Gene, and Phenotypic Analyses of the Gene-Disrupted Animal

  2006cited by this paper
• The insulin/PI 3-kinase pathway regulates salt chemotaxis learning in Caenorhabditis elegans.

  2006cited by this paper
• Insulin-like signaling and the neural circuit for integrative behavior in C. elegans.

  2006cited by this paper
• A recombineering pipeline for functional genomics applied to Caenorhabditis elegans

  2006cited by this paper
• Evolution of the Signaling System in Relaxin‐Family Peptides

  2005cited by this paper
• The Caenorhabditis elegans Heterochronic Regulator LIN-14 Is a Novel Transcription Factor That Controls the Developmental Timing of Transcription from the Insulin/Insulin-Like Growth Factor Gene ins-33 by Direct DNA Binding

  2005cited by this paper
• Metabolism, physiology and stress defense in three aging Ins/IGF‐1 mutants of the nematode Caenorhabditis elegans

  2005cited by this paper
• Systematic analysis of genes required for synapse structure and function

  2005cited by this paper
• Relaxin's physiological roles and other diverse actions.

  2004cited by this paper
• Insulin worms its way into the spotlight.

  2003cited by this paper
• A divergent INS protein in Caenorhabditis elegans structurally resembles human insulin and activates the human insulin receptor.

  2003cited by this paper
• daf-28 encodes a C. elegans insulin superfamily member that is regulated by environmental cues and acts in the DAF-2 signaling pathway.

  2003cited by this paper
• Statistical significance for genomewide studies

  2003cited by this paper
• Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans

  2003cited by this paper
• Long-Lived C. elegans daf-2 Mutants Are Resistant to Bacterial Pathogens

  2003cited by this paper
• Nutrient-dependent expression of insulin-like peptides from neuroendocrine cells in the CNS contributes to growth regulation in Drosophila.

  2002cited by this paper
• Ablation of Insulin-Producing Neurons in Flies: Growth and Diabetic Phenotypes

  2002cited by this paper
• Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family.

  2001influential reference
• An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control.

  2001cited by this paper
• Molecular cloning and characterization of a new insulin/IGF-like peptide of the nematode Caenorhabditis elegans.

  2000cited by this paper
• Pseudomonas aeruginosa killing of Caenorhabditis elegans used to identify P. aeruginosa virulence factors.

  1999cited by this paper
• Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans.

  1998influential reference
• Collective dynamics of ‘small-world’ networks

  1998cited by this paper
• daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans.

  1997cited by this paper
• Evolution of genetic redundancy

  1997cited by this paper
• The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans

  1997cited by this paper
• daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.

  1997cited by this paper
• Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress.

  1995cited by this paper
• A C. elegans mutant that lives twice as long as wild type

  1993cited by this paper
• Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans.

  1992cited by this paper
• Expression of insulin-like growth factor I in cultured rat hepatocytes: effects of insulin and growth hormone.

  1989cited by this paper
• The Caenorhabditis elegans dauer larva: developmental effects of pheromone, food, and temperature.

  1984cited by this paper

• Three Muscle-Specific DAF-16/FOXO Transcriptional Targets Activated by Reduced Insulin/IGF-1 Signaling

  2026cites this paper
• THE NEUROPEPTIDE NEUROMEDIN U RECEPTOR NMUR-1 BUFFERS INSULIN RECEPTOR SIGNALING IN BACTERIA-DEPENDENT C. ELEGANS SURVIVAL

  2025cites this paper
• Microbial Lipopolysaccharide Regulates Host Development Through Insulin/IGF-1 Signaling

  2025cites this paper
• The insulin-like peptide INS-27 mediates a muscle-to-neuron feedback signal coupling muscle activity with AMPA receptor trafficking

  2025cites this paper
• Gut epithelium modifies enteric behaviors during nutritional adversity via distinct peptidergic signaling axes

  2025cites this paper
• Body-wide synchronization of insulin-signaling dependent DAF-16/FOXO nuclear translocation pulses correlated with C. elegans growth

  2025cites this paper
• Transcriptomic insights into the healthspan-enhancing effects of C. chinensis seed and E. ulmoides bark extracts in Caenorhabditis elegans

  2025cites this paper
• Nictation behavior in nematodes

  2025cites this paper
• C. elegans insulin-like peptides.

  2024influential citation
• The signaling landscape of insulin-like growth factor 1

  2024cites this paper
• Sensory integration of food and population density during the diapause exit decision involves insulin-like signaling in Caenorhabditis elegans

  2024cites this paper
• Systematic mapping of organism-scale gene-regulatory networks in aging using population asynchrony.

  2024cites this paper
• Bacterial vitamin B6 is required for post-embryonic development in C. elegans

  2024cites this paper
• Sensory integration of food availability and population density during the diapause exit decision involves insulin-like signaling in Caenorhabditis elegans

  2024influential citation
• Adult single-nucleus neuronal transcriptomes of insulin signaling mutants reveal regulators of behavior and learning

  2024cites this paper
• Specific sensory neurons and insulin-like peptides modulate food type-dependent oogenesis and fertilization in Caenorhabditis elegans

  2023cites this paper
• Comparative Biochemistry and Physiology-Part A: Molecular & Integrative Physiology Special Issue: Comparative Models in Biomedical Research Invited Review C. elegans as a model organism to study female reproductive health

  2023cites this paper
• ADAR-mediated regulation of PQM-1 expression in neurons impacts gene expression throughout C. elegans and regulates survival from hypoxia

  2023cites this paper
• The C. elegans truncated insulin receptor DAF-2B regulates survival of L1 arrested larvae

  2023cites this paper
• Control of C. elegans growth arrest by stochastic, yet synchronized DAF-16/FOXO nuclear translocation pulses

  2023cites this paper
• Chemical synthesis of insulin‐like peptide 1 and its potential role in vitellogenesis of the kuruma prawn Marsupenaeus japonicus

  2023cites this paper
• The neurobiology of insulin-like growth factor I: From neuroprotection to modulation of brain states

  2023cites this paper
• Title: ADARs employ a neural-specific mechanism to regulate PQM-1 expression and survival from hypoxia Short Title: ADAR-mediated gene regulation affects hypoxia survival

  2023cites this paper
• ADARs employ a neural-specific mechanism to regulate PQM-1 expression and survival from hypoxia

  2023cites this paper
• Biological resilience and aging: Activation of stress response pathways contributes to lifespan extension.

  2023cites this paper
• The G protein-coupled receptor neuropeptide receptor-15 modulates larval development via the transforming growth factor-β DAF-7 protein in Caenorhabditis elegans.

  2023cites this paper
• The SR protein RSP-2 influences expression of the truncated insulin receptor DAF-2B in Caenorhabditis elegans

  2023cites this paper
• Diet-responsive transcriptional regulation of insulin in a single neuron controls systemic metabolism

  2022cites this paper
• Dauer fate in a Caenorhabditis elegans Boolean network model

  2022cites this paper
• Insulin and insulin-like growth factor-I receptors in astrocytes exert different effects on behavior and Alzheimer´s-like pathology

  2022cites this paper
• Meta-Analysis of Caenorhabditis elegans Transcriptomics Implicates Hedgehog-Like Signaling in Host-Microbe Interactions

  2022cites this paper
• Multiple insulin-like peptides in the gonads of the kuruma prawn Marsupenaeus japonicus

  2022cites this paper
• Conserved neuropeptidergic regulation of intestinal integrity in invertebrate models of aging

  2022cites this paper
• Invited review: Unearthing the mechanisms of age-related neurodegenerative disease using Caenorhabditis elegans.

  2022cites this paper
• C. elegans as a model organism to study female reproductive health.

  2022cites this paper
• Nutritional control of postembryonic development progression and arrest in Caenorhabditis elegans.

  2021cites this paper
• C. elegans: out on an evolutionary limb

  2021cites this paper
• Hormonal Regulation of Diapause and Development in Nematodes, Insects, and Fishes

  2021cites this paper
• daf-16/FOXO blocks adult cell fate in Caenorhabditis elegans dauer larvae via lin-41/TRIM71

  2021cites this paper
• Natural variation in the irld gene family affects starvation resistance in C. elegans

  2021cites this paper
• Natural variation in the irld gene family affects insulin/IGF signaling and starvation resistance

  2021cites this paper
• GABAergic synapses suppress intestinal innate immunity via insulin signaling in Caenorhabditis elegans

  2021cites this paper
• Natural genetic variation drives microbiome selection in the Caenorhabditis elegans gut

  2021cites this paper
• Aging Regulated Through a Stability Model of Insulin/Insulin Growth Factor Receptor Function

  2021cites this paper
• An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in C. elegans

  2020cites this paper
• DAF-16/FoxO in Caenorhabditis elegans and Its Role in Metabolic Remodeling

  2020cites this paper
• Nutrient Sensing and Response Drive Developmental Progression in Caenorhabditis elegans.

  2020cites this paper
• Caenorhabditis elegans processes sensory information to choose between freeloading and self-defense strategies

  2020cites this paper
• mRNA decapping is an evolutionarily conserved modulator of neuroendocrine signaling that controls development and ageing

  2020cites this paper
• Population Density Modulates the Duration of Reproduction of C. elegans.

  2020cites this paper
• Feeding state functionally reconfigures a sensory circuit to drive thermosensory behavioral plasticity

  2020cites this paper
• Neurogenetics of nictation, a dispersal strategy in nematodes

  2020cites this paper
• Neuromodulators: an essential part of survival

  2020cites this paper
• Starvation Responses Throughout the Caenorhabditis elegans Life Cycle

  2020cites this paper
• Cell Non-autonomous Function of daf-18/PTEN in the Somatic Gonad Coordinates Somatic Gonad and Germline Development in C. elegans Dauer Larvae.

  2019cites this paper
• Function and tissue focus of daf-18/PTEN in maintaining blast cell multipotency and quiescence in Caenorhabditis elegans dauer larvae

  2019cites this paper
• DAF‐16 stabilizes the aging transcriptome and is activated in mid‐aged Caenorhabditis elegans to cope with internal stress

  2019cites this paper
• Deep phenotyping in C. elegans

  2019cites this paper
• Axonal Transport Of An Insulin-Like Peptide Mrna Promotes Stress Recovery In C. Elegans

  2019cites this paper
• Pheromones Modulate Learning by Regulating the Balanced Signals of Two Insulin-like Peptides.

  2019cites this paper
• Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain

  2019cites this paper
• DAF-16: FOXO in the Context of C. elegans.

  2018cites this paper
• Regulation of reproduction and longevity by nutrient-sensing pathways

  2018cites this paper
• Nutritional Control of the Germline Development in Caenorhabditis elegans

  2018cites this paper
• Energy Scarcity Promotes a Brain-wide Sleep State Modulated by Insulin Signaling in C. elegans

  2018cites this paper
• Growth dynamics and size determination in Hydra

  2018cites this paper
• Drosophila insulin-like peptide dilp1 increases lifespan and glucagon-like Akh expression epistatic to dilp2

  2018influential citation
• Signal Transduction Pathways in Ageing.

  2018cites this paper
• Comparison of physiological functions of antagonistic insulin-like peptides, INS-23 and INS-18, in Caenorhabditis elegans

  2018cites this paper
• Drosophila insulin‐like peptide dilp1 increases lifespan and glucagon‐like Akh expression epistatic to dilp2

  2018cites this paper
• Temporal pattern of neuronal insulin release during Caenorhabditis elegans aging: Role of redox homeostasis

  2018cites this paper
• Pervasive Positive and Negative Feedback Regulation of Insulin-Like Signaling in Caenorhabditis elegans

  2018cites this paper
• Food perception without ingestion leads to metabolic changes and irreversible developmental arrest in C. elegans

  2018cites this paper
• A functional study of all 40 Caenorhabditis elegans insulin-like peptides

  2018influential citation
• A functional study of all 40 C. elegans insulin-like peptides

  2018cites this paper
• Diverse insulin-like peptides in Caenorhabditis elegans

  2017cites this paper
• Regulation of reproduction and longevity by nutrient-sensing pathways

  2017cites this paper
• The cell non-autonomous function of ATG-18 is essential for neuroendocrine regulation of Caenorhabditis elegans lifespan

  2017cites this paper
• Rictor/TORC2 mediates gut-to-brain signaling in the regulation of phenotypic plasticity in C. elegans

  2017cites this paper
• A histone H4 lysine 20 methyltransferase couples environmental cues to sensory neuron control of developmental plasticity

  2017cites this paper
• Review of Insulin-Like Growth Factor 1 Signaling Pathway and Its Role in Protection against Brain Diseases

  2017cites this paper
• Critical Genes Regulated by FoxO Transcription Factors in Life Span Control

  2017cites this paper
• Longevity control by the nervous system: Sensory perception, stress response and beyond

  2017cites this paper
• Role of Histone Methyltransferase SET-4 in Developmental Plasticity and Longevity

  2017cites this paper
• Dauer Formation and Ageing

  2017cites this paper
• Longevity Regulation by Insulin/IGF-1 Signalling

  2017cites this paper
• Regulation of a hitchhiking behavior by neuronal insulin and TGF-β signaling in the nematode Caenorhabditis elegans.

  2017cites this paper
• A network of insulin peptides regulate glucose uptake by astrocytes: Potential new druggable targets for brain hypometabolism.

  2017cites this paper
• Neuronal function of the mRNA decapping complex determines survival of Caenorhabditis elegans at high temperature through temporal regulation of heterochronic gene expression

  2017cites this paper
• The role of insulin/IGF-1 signaling in the longevity of model invertebrates, C. elegans and D. melanogaster

  2016cites this paper
• L1 arrest, daf-16/FoxO and nonautonomous control of post-embryonic development

  2016influential citation
• Diapause is associated with a change in the polarity of secretion of insulin-like peptides

  2016cites this paper
• Food-derived sensory cues modulate longevity via distinct neuroendocrine insulin-like peptides

  2016influential citation
• Cell-Autonomous and Non-Cell-Autonomous Regulation of a Feeding State-Dependent Chemoreceptor Gene via MEF-2 and bHLH Transcription Factors

  2016cites this paper
• Aging Mechanisms

  2015cites this paper
• Genes and Pathways That Influence Longevity in Caenorhabditis elegans

  2015cites this paper
• The Influence of the Insulin-Like Gene Family and Diet-Drug Interactions on Caenorhabditis elegans Physiology: A Dissertation

  2015cites this paper
• Neural mechanisms of gait regulation and olfactory plasticity in Caenorhabditis elegans

  2015cites this paper
• Correction: Feeding state-dependent regulation of developmental plasticity via CaMKI and neuroendocrine signaling

  2015cites this paper
• A peroxiredoxin, PRDX-2, is required for insulin secretion and insulin/IIS-dependent regulation of stress resistance and longevity

  2015cites this paper