title: Robustness and epistasis in the C. elegans vulval signaling network revealed by pathway dosage modulation.
abstract: Biological systems may perform reproducibly to generate invariant outcomes, despite external or internal noise. One example is the C. elegans vulva, in which the final cell fate pattern is remarkably robust. Although this system has been extensively studied and the molecular network underlying cell fate specification is well understood, very little is known in quantitative terms. Here, through pathway dosage modulation and single molecule fluorescence in situ hybridization, we show that the system can tolerate a 4-fold variation in genetic dose of the upstream signaling molecule LIN-3/epidermal growth factor (EGF) without phenotypic change in cell fate pattern. Furthermore, through tissue-specific dosage perturbations of the EGF and Notch pathways, we determine the first-appearing patterning errors. Finally, by combining different doses of both pathways, we explore how quantitative pathway interactions influence system behavior. Our results highlight the feasibility and significance of launching experimental studies of robustness and quantitative network analysis in genetically tractable, multicellular eukaryotes.
authors: Institute of Biology of the Ecole Normale Supérieure, 46 rue d'Ulm, 75230 Paris Cedex 05, France.
authors: Michalis
authors: M
authors: Barkoulas
authors: Jeroen S
authors: JS
authors: van Zon
authors: Josselin
authors: J
authors: Milloz
authors: Alexander
authors: A
authors: van Oudenaarden
authors: Marie-Anne
authors: MA
authors: Félix
mesh_terms: D000818:Animals; D019521:Body Patterning; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D004627:Embryonic Induction; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D004843:Epistasis, Genetic; D005260:Female; D018628:Gene Dosage; D017404:In Situ Hybridization, Fluorescence; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014844:Vulva / Q000166:cytology / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; C082460:Lin-12 protein, C elegans; D008565:Membrane Proteins; D051880:Receptors, Notch; C075912:Lin-3 protein, C elegans; D004815:Epidermal Growth Factor