title: An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology.
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.
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, United Kingdom.
authors.forename: Diana Andrea
authors.initials: DA
authors.lastname: Fernandes de Abreu
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, United Kingdom.
authors.forename: Antonio
authors.initials: A
authors.lastname: Caballero
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; Biozentrum, University of Basel, Basel, Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Fardel
authors.affiliation: Dept of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stroustrup
authors.affiliation: Dept of Organismic and Evolutionary Biology, The Center for Brain Science, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Zhunan
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics and Dept of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Kyunghwa
authors.initials: K
authors.lastname: Lee
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics and Dept of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: William D
authors.initials: WD
authors.lastname: Keyes
authors.affiliation: Dept of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: Nash
authors.affiliation: Dept of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Isaac F
authors.initials: IF
authors.lastname: López-Moyado
authors.affiliation: Research and Innovation Center, Fondazione Edmund Mach, San Michele all'Adige, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Vaggi
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Astrid
authors.initials: A
authors.lastname: Cornils
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Regenass
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; Biozentrum, University of Basel, Basel, Basel, Switzerland.
authors.forename: Anca
authors.initials: A
authors.lastname: Neagu
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Ivan
authors.initials: I
authors.lastname: Ostojic
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, United Kingdom.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Dept of Biological Sciences, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Deniz
authors.initials: D
authors.lastname: Sifoglu
authors.affiliation: Dept of Organismic and Evolutionary Biology, The Center for Brain Science, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Dept of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Walter
authors.initials: W
authors.lastname: Fontana
authors.affiliation: School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Hang
authors.initials: H
authors.lastname: Lu
authors.affiliation: Research and Innovation Center, Fondazione Edmund Mach, San Michele all'Adige, Italy; Institute for Mathematical and Molecular Biomedicine, King's College London, London, United Kingdom; Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
authors.forename: Attila
authors.initials: A
authors.lastname: Csikasz-Nagy
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics and Dept of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Coleen T
authors.initials: CT
authors.lastname: Murphy
authors.affiliation: Max Planck Institute for Biology of Ageing, Koeln, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Antebi
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, United Kingdom.
authors.forename: Eric
authors.initials: E
authors.lastname: Blanc
authors.affiliation: Dept of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Javier
authors.initials: J
authors.lastname: Apfeld
authors.affiliation: Dept of Organismic and Evolutionary Biology, The Center for Brain Science, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; Dept of Biological Sciences, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Joy
authors.initials: J
authors.lastname: Alcedo
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, United Kingdom.
authors.forename: Queelim
authors.initials: Q
authors.lastname: Ch'ng
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D053263:Gene Regulatory Networks; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D008136:Longevity / Q000235:genetics; D010641:Phenotype; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013002:Somatomedins / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D007328:Insulin; D013002:Somatomedins; C424903:ins-1 protein, C elegans; D011972:Receptor, Insulin