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

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 7

Tnc expression directly modulates Pdgfrβ expression.

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Tnc expression directly modulates Pdgfrβ expression. (A–C) Treatment of ...
(A–C) Treatment of lung explants from E11.5 embryos with a Tnc-blocking antibody reduced Pdgfrβ expression (arrows) by immunohistochemistry (A and B) and reduced both Pdgfrα and Pdgfrβ expression by Q-PCR (C). The white dotted lines in A and B denote the external outline of lung explant; yellow dotted lines denote developing airways. (D) Antibody-mediated blocking of Tnc function reduced lung mesenchymal proliferation. (E) Tnc protein treatment of Pac-1 cells led to increased Pdgfrβ but not Pdgfrα expression by Q-PCR. (F) Tnc protein treatment of E11.5 mouse lung explants resulted in increased expression of both Pdgfrα and Pdgfrβ as detected by Q-PCR. (G–K) Treatment of lung explants with Wnt3a and either non-immune IgG (control IgG) or Tnc-blocking antibody (Tnc IgG) showed that blocking Tnc decreased Wnt3a-induced Pdgfrα and Pdgfrβ expression, as assessed by Q-PCR (G) and immunohistochemistry (H–K). (H–L) Blocking Tnc also inhibited the Wnt3a-induced increase in proliferation observed in lung explants as noticed by PO4-H3 immunostaining (green nuclei). *P < 0.001; **P < 0.03. Scale bars: 250 μm.