title: Wntless is required for peripheral lung differentiation and pulmonary vascular development.
abstract: Wntless (Wls), a gene highly conserved across the animal kingdom, encodes for a transmembrane protein that mediates Wnt ligand secretion. Wls is expressed in developing lung, wherein Wnt signaling is necessary for pulmonary morphogenesis. We hypothesize that Wls plays a critical role in modulating Wnt signaling during lung development and therefore affects processes critical for pulmonary morphogenesis. We generated conditional Wls mutant mice utilizing Shh-Cre and Dermo1-Cre mice to delete Wls in the embryonic respiratory epithelium and mesenchyme, respectively. Epithelial deletion of Wls disrupted lung branching morphogenesis, peripheral lung development and pulmonary endothelial differentiation. Epithelial Wls mutant mice died at birth due to respiratory failure caused by lung hypoplasia and pulmonary hemorrhage. In the lungs of these mice, VEGF and Tie2-angiopoietin signaling pathways, which mediate vascular development, were downregulated from early stages of development. In contrast, deletion of Wls in mesenchymal cells of the developing lung did not alter branching morphogenesis or early mesenchymal differentiation. In vitro assays support the concept that Wls acts in part via Wnt5a to regulate pulmonary vascular development. We conclude that epithelial Wls modulates Wnt ligand activities critical for pulmonary vascular differentiation and peripheral lung morphogenesis. These studies provide a new framework for understanding the molecular mechanisms underlying normal pulmonary vasculature formation and the dysmorphic pulmonary vasculature development associated with congenital lung disease.
authors.affiliation: The Perinatal Institute Division of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Cincinnati Children's Hospital Medical Center Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: Bridget
authors.initials: B
authors.lastname: Cornett
authors.forename: John
authors.initials: J
authors.lastname: Snowball
authors.forename: Brian M
authors.initials: BM
authors.lastname: Varisco
authors.forename: Richard
authors.initials: R
authors.lastname: Lang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Whitsett
authors.forename: Debora
authors.initials: D
authors.lastname: Sinner
mesh_terms: D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D047108:Embryonic Development; D004730:Endothelium, Vascular / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000098:blood supply* / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2; D043562:Receptors, G-Protein-Coupled; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein
chemical_list: C545200:Gpr177 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; C467480:vascular endothelial growth factor A, mouse; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse