| First Author | Goodwin AT | Year | 2023 |
| Journal | Development | Volume | 150 |
| Issue | 9 | PubMed ID | 37102682 |
| Mgi Jnum | J:335603 | Mgi Id | MGI:7482320 |
| Doi | 10.1242/dev.201046 | Citation | Goodwin AT, et al. (2023) Stretch regulates alveologenesis and homeostasis via mesenchymal Galphaq/11-mediated TGFbeta2 activation. Development 150(9):dev201046 |
| abstractText | Alveolar development and repair require tight spatiotemporal regulation of numerous signalling pathways that are influenced by chemical and mechanical stimuli. Mesenchymal cells play key roles in numerous developmental processes. Transforming growth factor-beta (TGFbeta) is essential for alveologenesis and lung repair, and the G protein alpha subunits Galphaq and Galpha11 (Galphaq/11) transmit mechanical and chemical signals to activate TGFbeta in epithelial cells. To understand the role of mesenchymal Galphaq/11 in lung development, we generated constitutive (Pdgfrb-Cre+/-;Gnaqfl/fl;Gna11-/-) and inducible (Pdgfrb-Cre/ERT2+/-;Gnaqfl/fl;Gna11-/-) mesenchymal Galphaq/11 deleted mice. Mice with constitutive Galphaq/11 gene deletion exhibited abnormal alveolar development, with suppressed myofibroblast differentiation, altered mesenchymal cell synthetic function, and reduced lung TGFbeta2 deposition, as well as kidney abnormalities. Tamoxifen-induced mesenchymal Galphaq/11 gene deletion in adult mice resulted in emphysema associated with reduced TGFbeta2 and elastin deposition. Cyclical mechanical stretch-induced TGFbeta activation required Galphaq/11 signalling and serine protease activity, but was independent of integrins, suggesting an isoform-specific role for TGFbeta2 in this model. These data highlight a previously undescribed mechanism of cyclical stretch-induced Galphaq/11-dependent TGFbeta2 signalling in mesenchymal cells, which is imperative for normal alveologenesis and maintenance of lung homeostasis. |
