title: An interplay of geometry and signaling enables robust lung branching morphogenesis.
abstract: Early branching events during lung development are stereotyped. Although key regulatory components have been defined, the branching mechanism remains elusive. We have now used a developmental series of 3D geometric datasets of mouse embryonic lungs as well as time-lapse movies of cultured lungs to obtain physiological geometries and displacement fields. We find that only a ligand-receptor-based Turing model in combination with a particular geometry effect that arises from the distinct expression domains of ligands and receptors successfully predicts the embryonic areas of outgrowth and supports robust branch outgrowth. The geometry effect alone does not support bifurcating outgrowth, while the Turing mechanism alone is not robust to noisy initial conditions. The negative feedback between the individual Turing modules formed by fibroblast growth factor 10 (FGF10) and sonic hedgehog (SHH) enlarges the parameter space for which the embryonic growth field is reproduced. We therefore propose that a signaling mechanism based on FGF10 and SHH directs outgrowth of the lung bud via a ligand-receptor-based Turing mechanism and a geometry effect.
authors.affiliation: Department of Biosystems, Science and Engineering (D-BSSE), ETH Zurich, Mattenstraße 26, 4058 Basel, Switzerland Swiss Institute of Bioinformatics (SIB), Mattenstraße 26, 4058 Basel, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Menshykau
authors.affiliation: R2D2/Retinoids, Reproduction, Developmental Diseases, Faculté de Médecine, 28 Place Henri Dunant, BP 38, 63001 Clermont-Ferrand Cedex, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Blanc
authors.affiliation: Department of Biosystems, Science and Engineering (D-BSSE), ETH Zurich, Mattenstraße 26, 4058 Basel, Switzerland Swiss Institute of Bioinformatics (SIB), Mattenstraße 26, 4058 Basel, Switzerland Developmental Genetics, Department Biomedicine, University of Basel, Mattenstraße 28, 4058 Basel, Switzerland.
authors.forename: Erkan
authors.initials: E
authors.lastname: Unal
authors.affiliation: R2D2/Retinoids, Reproduction, Developmental Diseases, Faculté de Médecine, 28 Place Henri Dunant, BP 38, 63001 Clermont-Ferrand Cedex, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Sapin
authors.affiliation: Department of Biosystems, Science and Engineering (D-BSSE), ETH Zurich, Mattenstraße 26, 4058 Basel, Switzerland Swiss Institute of Bioinformatics (SIB), Mattenstraße 26, 4058 Basel, Switzerland dagmar.iber@bsse.ethz.ch.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Iber
mesh_terms: D000818:Animals; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D008168:Lung / Q000196:embryology*; D051379:Mice; D008954:Models, Biological; D009024:Morphogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D059008:Time-Lapse Imaging
chemical_list: C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D053823:Hedgehog Proteins; C465570:Shh protein, mouse
keywords: Branching morphogenesis; Computational biology; Image-based modeling; Turing pattern