Mesodermal Deletion of Transforming Growth Factor-β Receptor II Disrupts Lung Epithelial Morphogenesis

Abstract

In vertebrates, Sonic hedgehog (Shh) and transforming growth factor-␤ (TGF-␤) signaling pathways occur in an overlapping manner in many morphogenetic processes. In vitro data indicate that the two pathways may interact. Whether such interactions occur during embryonic development remains unknown. Using embryonic lung morphogenesis as a model, we generated transgenic mice in which exon 2 of the T␤RII gene, which encodes the type II TGF-␤ receptor, was deleted via a mesodermal-specific Cre. Mesodermal-specific deletion of T␤RII (T␤RII ⌬/⌬ ) resulted in embryonic lethality. The lungs showed abnormalities in both number and shape of cartilage in trachea and bronchi. In the lung parenchyma, where epithelialmesenchymal interactions are critical for normal development, deletion of mesenchymal T␤RII caused abnormalities in epithelial morphogenesis. Failure in normal epithelial branching morphogenesis in the T␤RII ⌬/⌬ lungs caused cystic airway malformations. Interruption of the T␤RII locus in the lung mesenchyme increased mRNA for Patched and Gli-1, two downstream targets of Shh signaling, without alterations in Shh ligand levels produced in the epithelium. Therefore, we conclude that T␤RII-mediated signaling in the lung mesenchyme modulates transduction of Shh signaling that originates from the epithelium. To our knowledge, this is the first in vivo evidence for a reciprocal and novel mode of cross-communication between Shh and TGF-␤ pathways during embryonic development.

Sonic Hedgehog Signaling in the Lung. From Development to Disease

“…Knockout of transforming growth factor β receptor II, a receptor for TGFβ ligands that is involved in epithelial-mesenchymal communication during development, causes cystic lung with defective branching (115). Interestingly, the Hh signaling transcriptional targets Ptch1 and Gli1 were increased without altered Shh expression, suggesting the possibility of non-canonical pathway regulation.…”

Thrown off balance: the effect of antenatal inflammation on the developing lung and immune system

“…35 Interactions between TGF-␤, Shh, Wnt, FGFs, and BMPs have been described at multiple levels, both in normal lung development, remodeling, and disease. [114][115][116][117] Because of their importance in both lung development and remodeling, and likely also the development of BPD, regulatory molecules of these pathways may be of special interest for the development therapeutic interventions for BPD. 35,83,84 CTGF, for example, can induce Wnt-signaling, reciprocally switch on Smad signaling, and inhibit VEGF.…”

Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis

“…Previous studies have shown that conventional deletion of TβRII leads to early embryonic lethality (11), while mesenchymal deletion of TβRII results in gross abnormalities of trachea and lung (16). To study the role of TβRII specifically in lung epithelial cells, we crossed TβRII fl/fl females with Nkx2.1-cre male mice and backcrossed the heterozygotes to generate TβRII fl/fl ;Nkx2.1-cre (simply, TβRII Nkx2.1-cre ) progeny.…”