Stretch-induced alternative splicing of serum response factor promotes bronchial myogenesis and is defective in lung hypoplasia
Yan Yang, … , Ilana Ariel, Lucia Schuger
Yan Yang, … , Ilana Ariel, Lucia Schuger
Published December 1, 2000
Citation Information: J Clin Invest. 2000;106(11):1321-1330. https://doi.org/10.1172/JCI8893.
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Article

Stretch-induced alternative splicing of serum response factor promotes bronchial myogenesis and is defective in lung hypoplasia

Abstract

Smooth muscle (SM) develops only in organs and sites that sustain mechanical tensions. Therefore, we determined the role of stretch in mouse and human bronchial myogenesis. Sustained stretch induced expression of SM proteins in undifferentiated mesenchymal cells and accelerated the differentiation of cells undergoing myogenesis. Moreover, bronchial myogenesis was entirely controlled in lung organ cultures by the airway intraluminal pressure. Serum response factor (SRF) is a transcription factor critical for the induction of muscle-specific gene expression. Recently, a SRF-truncated isoform produced by alternative splicing of exon 5 has been identified (SRFΔ5). Here we show that undifferentiated mesenchymal cells synthesize both SRF and SRFΔ5 but that SRFΔ5 synthesis is suppressed during bronchial myogenesis in favor of increased SRF production. Stretch induces the same change in SRF alternative splicing, and its myogenic effect is abrogated by overexpressing SRFΔ5. Furthermore, human hypoplastic lungs related to conditions that hinder cell stretching continue to synthesize SRFΔ5 and show a marked decrease in bronchial and interstitial SM cells and their ECM product, tropoelastin. Taken together, our findings indicate that stretch plays a critical role in SM myogenesis and suggest that its decrease precludes normal bronchial muscle development.

Authors

Yan Yang, Safedin Beqaj, Paul Kemp, Ilana Ariel, Lucia Schuger

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(a) Immunoblot shows stretch-induced upregulation of SM-specific protein...
(a) Immunoblot shows stretch-induced upregulation of SM-specific protein synthesis in human lung mesenchymal cells undergoing myogenic differentiation. (b) Immunoblots show stimulation of SM protein synthesis in human fetal lung organ cultures by dextran-induced tissue stretching. In a and b the lungs were obtained from 18-week fetuses, after the onset of visceral and vascular SM differentiation. Therefore, the initial levels of SM protein are higher than in murine cells. (c and d) Immunohistochemistry shows SM α-actin in histological sections from human fetal lungs (18 weeks) cultured for 48 hours with 1% dextran in the culture medium outside the explant (c) and 1% dextran inside the airways (d). Notice the significant increment in bronchial SM cells in c compared with d (arrows). The vascular SM shows no differences (arrowheads). Results are representative of three experiments, each performed on quadruplicate lung explants per treatment. Bar, 20 μm.