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-Catenin regulates differentiation of respiratory epithelial cells in vivo

¹Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati; ²Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; ³Banyu Tsukubu Research Institute (Merck), Tsukuba, Japan; ⁴Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; and ⁵Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee

Submitted 15 April 2005 ; accepted in final form 14 July 2005

An activated form of -catenin [Catnb^(ex3)] was expressed in respiratory epithelial cells of the developing lung. Although morphogenesis was not altered at birth, air space enlargement and epithelial cell dysplasia were observed in the early postnatal period and persisted into adulthood. The Catnb^(ex3) protein caused squamous, cuboidal, and goblet cell dysplasia in intrapulmonary conducting airways. Atypical epithelial cells that stained for surfactant pro protein C (pro-SP-C) and had morphological characteristics of alveolar type II cells were observed in bronchioles of the transgenic mice. Catnb^(ex3) inhibited expression of Foxa2 and caused goblet cell hyperplasia associated with increased staining for mucins and the MUC5A/C protein. In vitro, both wild type and activated -catenin negatively regulated the expression of the Foxa2 promoter. Catnb^(ex3) also caused pulmonary tumors in adult mice. Activation of -catenin caused ectopic differentiation of alveolar type II-like cells in conducting airways, goblet cell hyperplasia, and air space enlargement, demonstrating a critical role for the Wnt/-catenin signal transduction pathway in the differentiation of the respiratory epithelium in the postnatal lung.

lung morphogenesis; tumorigenesis; goblet cell hyperplasia; air space enlargement

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