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TGF-β receptor II in epithelia versus mesenchyme plays distinct roles in the developing lung

¹ Developmental Biology Program, Children's Hospital Los Angeles, ² Dept of Ophthalmology, Keck School of Medicine, University of Southern California, ³ The Center of Craniofacial Molecular Biology, University of Southern California School of Dentistry, and, Los Angeles, CA, and ⁵ Vanderbilt-Ingram Cancer Center, Nashville, TN, USA, ⁴ Dept of Medicine, Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.

CORRESPONDENCE: W. Shi, Developmental Biology Program, Dept of Surgery, Childrens Hospital Los Angeles, 4650 Sunset Blvd, MS 35, Los Angeles, CA 90027, USA. Fax: 1 3233613613. E-mail: wshi{at}chla.usc.edu

Keywords: Lung alveolarisation, lung branching morphogenesis, transforming growth factor-β, transforming growth factor-β type II receptor

Received: December 6, 2007
Accepted February 21, 2008

Transforming growth factor (TGF)-β signalling plays important roles in regulating lung development. However, the specific regulatory functions of TGF-β signalling in developing lung epithelial versus mesenchymal cells are still unknown.

By immunostaining, the expression pattern of the TGF-β type II receptor (TβRII) was first determined in the developing mouse lung. The functions of TβRII in developing lung were then determined by conditionally knocking out TβRII in the lung epithelium of floxed-TβRII/surfactant protein C-reverse tetracycline transactivator/TetO-Cre mice versus mesenchyme of floxed-TβRII/Dermo1-Cre mice.

TβRII was expressed only in distal airway epithelium at early gestation (embryonic day (E)11.5), but in both airway epithelium and mesenchyme from mid-gestation (E14.5) to post-natal day 14. Abrogation of TβRII in mouse lung epithelium resulted in retardation of post-natal lung alveolarisation, with markedly decreased type I alveolar epithelial cells, while no abnormality in prenatal lung development was observed. In contrast, blockade of TβRII in mesoderm-derived tissues, including lung mesenchyme, resulted in mildly abnormal lung branching and reduced cell proliferation after mid-gestation, accompanied by multiple defects in other organs, including diaphragmatic hernia. The primary lung branching defect was verified in embryonic lung explant culture.

The novel findings of the present study suggest that transforming growth factor-β type II receptor-mediated transforming growth factor-β signalling plays distinct roles in lung epithelium versus mesenchyme to differentially control specific stages of lung development.