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

Smooth muscle (SM) develops only in organs and sites that sustain mechanica l 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;he differentiation of cells undergoing myogenesis. Moreover, bronchial myogenesis was entirely c ontrolled 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 prod uced by alternative splicing of exon 5 has been identified (SRF Delta5). He re we show that undifferentiated mesenchymal cells synthesize both SRF and SRF Delta5 but that SRF Delta5 synthesis is suppressed during bronchial myo genesis in favor of increased SRF production. Stretch induces the same chan ge in SRF alternative splicing, and its myogenic effect is abrogated by ove rexpressing SRF Delta5. Furthermore, human hypoplastic lungs related to con ditions that hinder cell stretching continue to synthesize SRF Delta5 and s how a marked decrease in bronchial and interstitial SM cells and their ECM product, tropoelastin. Taken together, our findings indicate that stretch p lays a critical role in SM myogenesis and suggest that its decrease preclud es normal bronchial muscle development.