Wnt signaling regulates smooth muscle precursor development in the mouse lung via a tenascin C/PDGFR pathway.
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.
Cohen
Ethan David
ED
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. cohene@mail.med.upenn.edu
Ihida-Stansbury
Kaori
K
Lu
Min Min
MM
Panettieri
Reynold A
RA
Jones
Peter Lloyd
PL
Morrisey
Edward E
EE
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
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
Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3299-304
12626757
Dev Biol. 1997 May 1;185(1):82-91
9169052
Am J Respir Cell Mol Biol. 2001 Jul;25(1):45-50
11472974
Hum Mol Genet. 2005 Oct 1;14(19):2779-86
16115819
Dev Biol. 2005 Nov 1;287(1):86-97
16169547
Circ Res. 2001 Jul 20;89(2):131-8
11463719
J Clin Invest. 2007 Jul;117(7):1794-804
17607356
J Biol Chem. 2002 Jun 7;277(23):21061-70
11914369
Eur J Immunol. 2006 Dec;36(12):3334-45
17125141
Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16626-30
18922767
Development. 2001 Apr;128(8):1253-64
11262227
J Biol Chem. 2003 Oct 10;278(41):40231-8
12885771
PLoS One. 2008 May 14;3(5):e2142
18478089
Am J Physiol Lung Cell Mol Physiol. 2003 May;284(5):L826-33
12533438
Dev Biol. 2005 Jul 1;283(1):226-39
15907834
Biochem Biophys Res Commun. 1995 May 5;210(1):165-73
7741738
J Histochem Cytochem. 2002 Mar;50(3):423-31
11850444
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8455-9
8710892
J Am Coll Cardiol. 2004 Jun 16;43(12 Suppl S):13S-24S
15194174
Development. 1999 Jun;126(14):3047-55
10375497
Mol Cell Biol. 2005 Jun;25(12):5022-30
15923619
Int Arch Allergy Immunol. 2006;141(1):37-46
16804324
Nat Genet. 2000 Sep;26(1):81-4
10973254
Genesis. 2005 Apr;41(4):179-84
15789423
Dev Biol. 2005 Jan 15;277(2):316-31
15617677
Am J Hum Genet. 2000 Sep;67(3):737-44
10903931
Development. 2008 May;135(9):1625-34
18367557
J Clin Invest. 2005 Oct;115(10):2811-21
16200212
Chest. 2003 Mar;123(3 Suppl):428S-9S
12629018
Dev Biol. 1998 Oct 15;202(2):228-34
9769174
Dev Biol. 2002 Aug 1;248(1):68-81
12142021
Am J Pathol. 1997 Apr;150(4):1349-60
9094991
Development. 2006 May;133(9):1611-24
16613830
Development. 2002 Oct;129(20):4831-42
12361974
Am J Physiol Lung Cell Mol Physiol. 2006 Oct;291(4):L694-702
16782755
Circ Res. 1996 Dec;79(6):1131-42
8943951
Nat Genet. 2008 Jul;40(7):862-70
18536717
J Cell Biol. 1997 Oct 6;139(1):279-93
9314546
Am J Physiol Lung Cell Mol Physiol. 2005 Dec;289(6):L971-9
16040629
Mol Cell Biol. 2002 Feb;22(4):1172-83
11809808