1. Abrogation of mesenchyme-specific TGF-β signaling results in lung malformation with prenatal pulmonary cysts in mice
- Author
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Ling Chu, Matthew E. Thornton, Joanne Chiu, Martin Kolb, Jianlin Lou, Yongfeng Luo, Qing Miao, Wei Shi, Brendan H. Grubbs, and Hui Chen
- Subjects
Lung Diseases ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Genetically modified mouse ,Physiology ,Organogenesis ,Mesenchyme ,Mice, Transgenic ,Protein Serine-Threonine Kinases ,Biology ,Mesoderm ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,TGF beta signaling pathway ,Morphogenesis ,medicine ,Animals ,Lung ,Cysts ,Mesenchymal stem cell ,Receptor, Transforming Growth Factor-beta Type II ,Gene Expression Regulation, Developmental ,Epithelial Cells ,Cell Biology ,respiratory system ,Embryonic stem cell ,respiratory tract diseases ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,Signal transduction ,Receptors, Transforming Growth Factor beta ,030217 neurology & neurosurgery ,Research Article ,Transforming growth factor - Abstract
The TGF-β signaling pathway plays a pivotal role in controlling organogenesis during fetal development. Although the role of TGF-β signaling in promoting lung alveolar epithelial growth has been determined, mesenchymal TGF-β signaling in regulating lung development has not been studied in vivo due to a lack of genetic tools for specifically manipulating gene expression in lung mesenchymal cells. Therefore, the integral roles of TGF-β signaling in regulating lung development and congenital lung diseases are not completely understood. Using a Tbx4 lung enhancer-driven Tet-On inducible Cre transgenic mouse system, we have developed a mouse model in which lung mesenchyme-specific deletion of TGF-β receptor 2 gene ( Tgfbr2) is achieved. Reduced airway branching accompanied by defective airway smooth muscle growth and later peripheral cystic lesions occurred when lung mesenchymal Tgfbr2 was deleted from embryonic day 13.5 to 15.5, resulting in postnatal death due to respiratory insufficiency. Although cell proliferation in both lung epithelium and mesenchyme was reduced, epithelial differentiation was not significantly affected. Tgfbr2 downstream Smad-independent ERK1/2 may mediate these mesenchymal effects of TGF-β signaling through the GSK3β-β-catenin-Wnt canonical pathway in fetal mouse lung. Our study suggests that Tgfbr2-mediated TGF-β signaling in prenatal lung mesenchyme is essential for lung development and maturation, and defective TGF-β signaling in lung mesenchyme may be related to abnormal airway branching morphogenesis and congenital airway cystic lesions.
- Published
- 2021