title: Wnt signaling regulates smooth muscle precursor development in the mouse lung via a tenascin C/PDGFR pathway.
abstract: Paracrine signaling from lung epithelium to the surrounding mesenchyme is important for lung SMC development and function and is a contributing factor in an array of pulmonary diseases such as bronchopulmonary dysplasia, pulmonary hypertension, and asthma. Wnt7b, which is exclusively expressed in the lung epithelium, is important for lung vascular smooth muscle integrity, but the underlying mechanism by which Wnt signaling regulates lung SMC development is unclear. In this report, we have demonstrated that Wnt7b regulates a program of mesenchymal differentiation in the mouse lung that is essential for SMC development. Genetic loss-of-function studies showed that Wnt7b and beta-catenin were required for expression of Pdgfralpha and Pdgfrbeta and proliferation in pulmonary SMC precursors. In contrast, gain-of-function studies showed that activation of Wnt signaling increased the expression of both Pdgfralpha and Pdgfrbeta as well as the proliferation of SMC precursors. We further showed that the effect on Pdgfr expression was, in part, mediated by direct transcriptional regulation of the ECM protein tenascin C (Tnc), which was necessary and sufficient for Pdgfralpha/beta expression in lung explants. Moreover, this pathway was highly upregulated in a mouse model of asthma and in lung tissue from patients with pulmonary hypertension. Together, these data define a Wnt/Tnc/Pdgfr signaling axis that is critical for smooth muscle development and disease progression in the lung.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. cohene@mail.med.upenn.edu
authors.forename: Ethan David
authors.initials: ED
authors.lastname: Cohen
authors.forename: Kaori
authors.initials: K
authors.lastname: Ihida-Stansbury
authors.forename: Min Min
authors.initials: MM
authors.lastname: Lu
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.forename: Peter Lloyd
authors.initials: PL
authors.lastname: Jones
authors.forename: Edward E
authors.initials: EE
authors.lastname: Morrisey
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D019063:Tenascin / Q000378:metabolism*; D051153:Wnt Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D011518:Proto-Oncogene Proteins; D019063:Tenascin; D051153:Wnt Proteins; C095937:Wnt7b protein, mouse; D051176:beta Catenin; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta
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