The Transforming growth factor (Tgf)-beta signalling pathway is a key regulator of lung homeostasis as it is involved in organ development, as well as in pathological conditions of stunted lung growth such as bronchopulmonary dysplasia (BPD). The accessory Tgf-beta receptor 3 (Tgfbr3), also known as betaglycan, is a key ancillary molecule in the Tgf-beta pathway that has been documented to be essential for the development of the mouse embryo. The siRNA-mediated knockdown of Tgfbr3 resulted in an increase in the proliferation and migration of primary mouse lung fibroblasts, independently of Tgf-beta ligand stimulation. To study the role of Tgfbr3 in post-natal lung development, a mouse strain carrying a floxed Tgfbr3 allele was created. The Tgfbr3 floxed mouse strain was crossed to mice expressing Cre recombinase specific to cells with smooth muscle properties, such as smooth muscle myosin heavy chain (SMMHC)+ cells, and platelet-derived growth factor receptor (PDGFR)alpha+ cells. Temporal conditional knockout of Tgfbr3 was induced in mouse pups at post-natal day (P)1 and P2, by administration of tamoxifen. Stereological analysis of lung structure at P7 revealed significantly decreased alveolarisation of the lung in both knockout mouse lines. It was demonstrated that genetic changes following in vivo knockout of Tgfbr3 from fibroblasts with smooth muscle cell properties include a pronounced increase in the expression of fibronectin, proliferating cell nuclear antigen and beta-catenin protein. A Tgfbr3-specific knockout in Tie2+ cells led to impaired lung development, with a decreased septal thickness and decreased vessel wall thickness. The potential downstream signalling mechanisms were investigated by whole-transcriptome microarray analysis following in vitro knockdown of Tgfbr3. Limb bud and heart (Lbh) was selected as a candidate gene that was demonstrated to have a significant impact on the migration and proliferation of primary mouse lung fibroblasts. This led to the study of the lung phenotype of the global Lbh knockout (KO) mice, which exhibited an increase in septal thickness. Data taken together data suggest novel role for Tgfbr3 in lung development and underscore it as a central regulator of late lung development.
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