TGF- receptor II in Epithelia Versus Mesenchyme Plays Distinct Role in Developing Lung

¹ Developmental Biology Program, Childrens Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027
² Dept of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
³ The Center of Craniofacial Molecular Biology, University of Southern California School of Dentistry, 2250 Alcazar St., Los Angeles, CA 90033
⁴ Dept of Medicine, Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada L8N 4A6
⁵ Vanderbilt-Ingram Cancer Center, 691 Preston Building, Nashville, TN 37232-6838
⁶ Developmental Biology Program, Childrens Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027; and The Center of Craniofacial Molecular Biology, University of Southern California School of Dentistry, 2250 Alcazar St., Los Angeles, CA 90033

^* To whom correspondence should be addressed. E-mail: wshi{at}chla.usc.edu.

	Abstract

TGF- signaling plays important roles in regulating lung development. However, the specific regulatory functions of TGF- signaling in developing lung epithelial versus mesenchymal cells are still unknown.

By immunostaining, we first determined the expression pattern of TGF- type II receptor (TRII) in developing mouse lung. The functions of TRII in developing lung were then determined by conditionally knocking out TRII in lung epithelium of floxed-TRII/SPC-rtTA/TetO-Cre mice versus mesenchyme of floxed-TRII/Dermo1-Cre mice, respectively.

TRII was expressed only in distal airway epithelium at early gestation (E11.5), but in both airway epithelium and mesenchyme from mid-gestation (E14.5) to postnatal day 14. Abrogation of TRII in mouse lung epithelium resulted in retardation of postnatal lung alveolarization with markedly decreased type I alveolar epithelial cells, while no abnormality in prenatal lung development was observed. In contrast, blockade of TRII 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.

Our novel findings suggest that TRII-mediated TGF- signaling plays distinct roles in lung epithelium versus mesenchyme to differentially control specific stages of lung development.

Keywords:  Lung alveolarization, lung branching morphogenesis, TGF-, TGF- receptor II