title: Shape self-regulation in early lung morphogenesis.
abstract: The arborescent architecture of mammalian conductive airways results from the repeated branching of lung endoderm into surrounding mesoderm. Subsequent lung's striking geometrical features have long raised the question of developmental mechanisms involved in morphogenesis. Many molecular actors have been identified, and several studies demonstrated the central role of Fgf10 and Shh in growth and branching. However, the actual branching mechanism and the way branching events are organized at the organ scale to achieve a self-avoiding tree remain to be understood through a model compatible with evidenced signaling. In this paper we show that the mere diffusion of FGF10 from distal mesenchyme involves differential epithelial proliferation that spontaneously leads to branching. Modeling FGF10 diffusion from sub-mesothelial mesenchyme where Fgf10 is known to be expressed and computing epithelial and mesenchymal growth in a coupled manner, we found that the resulting laplacian dynamics precisely accounts for the patterning of FGF10-induced genes, and that it spontaneously involves differential proliferation leading to a self-avoiding and space-filling tree, through mechanisms that we detail. The tree's fine morphological features depend on the epithelial growth response to FGF10, underlain by the lung's complex regulatory network. Notably, our results suggest that no branching information has to be encoded and that no master routine is required to organize branching events at the organ scale. Despite its simplicity, this model identifies key mechanisms of lung development, from branching to organ-scale organization, and could prove relevant to the development of other branched organs relying on similar pathways.
authors.affiliation: Laboratoire Matière & Systèmes Complexes, UMR CNRS 7057, University Paris Diderot, Paris, France. raphael.clement@unice.fr
authors.forename: Raphaël
authors.initials: R
authors.lastname: Clément
authors.forename: Pierre
authors.initials: P
authors.lastname: Blanc
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mauroy
authors.forename: Vincent
authors.initials: V
authors.lastname: Sapin
authors.forename: Stéphane
authors.initials: S
authors.lastname: Douady
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D020545:Respiratory Mucosa / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse