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Wnt signaling regulates smooth muscle precursor development in the mouse lung via a tenascin C/PDGFR pathway
Ethan David Cohen, … , Peter Lloyd Jones, Edward E. Morrisey
Ethan David Cohen, … , Peter Lloyd Jones, Edward E. Morrisey
Published August 17, 2009
Citation Information: J Clin Invest. 2009;119(9):2538-2549. https://doi.org/10.1172/JCI38079.
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Research Article Vascular biology

Wnt signaling regulates smooth muscle precursor development in the mouse lung via a tenascin C/PDGFR pathway

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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 β-catenin were required for expression of Pdgfrα and Pdgfrβ and proliferation in pulmonary SMC precursors. In contrast, gain-of-function studies showed that activation of Wnt signaling increased the expression of both Pdgfrα and Pdgfrβ 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 Pdgfrα/β 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

Ethan David Cohen, Kaori Ihida-Stansbury, Min Min Lu, Reynold A. Panettieri, Peter Lloyd Jones, Edward E. Morrisey

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Figure 2

Wnt7b and β-catenin signaling regulates Pdgfrα and Pdgfrβ expression in the lung.

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Wnt7b and β-catenin signaling regulates Pdgfrα and Pdgfrβ expression in ...
(A–D) Immunostaining for Pdgfrβ expression in the developing lungs of wild-type (A and C) and Wnt7blacZ-null mutants (B and D) at E10.5 (A and B) and in developing blood vessels (arrows) at E12.5 (C and D). (E) Q-PCR for Pdgfrα and Pdgfrβ expression at E10.5. (F–I) Immunostaining for Pdgfrα expression in the developing lungs of wild-type (F and H) and Wnt7blacZ-null mutants (G and I) at E10.5 (F and G) and E12.5 (H and I). (J) BAT-GAL Wnt reporter activity at E10.5 in the mesenchyme of the lung in an overlapping region where Pdgfrβ expression was observed. (K and L) Immunostaining for Pdgfrβ expression in wild-type (K) and SM22α-cre:Ctnnb1flox/flox mutants (L) at E12.5. (M) Q-PCR for Pdgfrα and Pdgfrβ expression in wild-type and SM22α-cre:Ctnnb1flox/flox mutants at E10.5. (N) Q-PCR for axin2, Pdgfrα, and Pdgfrβ expression from the lung buds of NaCl- and LiCl-treated embryos at E10.5. (O–R) SM22α immunostaining in lungs of NaCl- and LiCl-treated E15.5 embryos. (S) Q-PCR for SM-MHC and calponin expression from the lung buds of NaCl- and LiCl-treated embryos at E14.5. ai, airway. *P < 0.01. Scale bars: 250 μm (A–D, F, G, and J), 150 μm (H, I, K, and L), 100 μm (O–R).

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