title: Mesothelial- and epithelial-derived FGF9 have distinct functions in the regulation of lung development.
abstract: Fibroblast growth factor (FGF) 9 is a secreted signaling molecule that is expressed in lung mesothelium and epithelium and is required for lung development. Embryos lacking FGF9 show mesenchymal hypoplasia, decreased epithelial branching and, by the end of gestation, hypoplastic lungs that cannot support life. Mesenchymal FGF signaling interacts with β-catenin-mediated WNT signaling in a feed-forward loop that functions to sustain mesenchymal FGF responsiveness and mesenchymal WNT/β-catenin signaling. During pseudoglandular stages of lung development, Wnt2a and Wnt7b are the canonical WNT ligands that activate mesenchymal WNT/β-catenin signaling, whereas FGF9 is the only known ligand that signals to mesenchymal FGF receptors (FGFRs). Here, we demonstrate that mesothelial- and epithelial-derived FGF9, mesenchymal Wnt2a and epithelial Wnt7b have unique functions in lung development in mouse. Mesothelial FGF9 and mesenchymal WNT2A are principally responsible for maintaining mesenchymal FGF-WNT/β-catenin signaling, whereas epithelial FGF9 primarily affects epithelial branching. We show that FGF signaling is primarily responsible for regulating mesenchymal proliferation, whereas β-catenin signaling is a required permissive factor for mesenchymal FGF signaling.
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Yin
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D004848:Epithelium / Q000378:metabolism*; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D051525:Fibroblast Growth Factor 9 / Q000378:metabolism*; D008168:Lung / Q000033:anatomy & histology / Q000196:embryology* / Q000254:growth & development* / Q000473:pathology; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D038081:Organogenesis / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051154:Wnt2 Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D051526:Fibroblast Growth Factor 10; D051525:Fibroblast Growth Factor 9; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D051154:Wnt2 Protein; D051176:beta Catenin; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse; C561116:WNT2A protein, mouse; C095937:Wnt7b protein, mouse