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Am J Physiol Lung Cell Mol Physiol (July 22, 2005). doi:10.1152/ajplung.00172.2005
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Submitted on April 15, 2005
Accepted on July 14, 2005

{beta}-CATENIN REGULATES DIFFERENTIATION OF RESPIRATORY EPITHELIAL CELLS IN VIVO

Michael L Mucenski1*, Jennifer M Nation2, Angela R Thitoff2, Valerie Besnard2, Yan Xu1, Susan E Wert1, Naomoto Harada3, Makoto M Taketo4, Mildred T Stahlman5, and Jeffrey A Whitsett1

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

* To whom correspondence should be addressed. E-mail: michael.mucenski{at}cchmc.org.

An activated form of {beta}-catenin (Catnb{Delta}(ex3)) was expressed in respiratory epithelial cells of the developing lung. While morphogenesis was not altered at birth, airspace enlargement and epithelial cell dysplasia were observed in the early postnatal period and persisted into adulthood. The Catnb{Delta}(ex3) protein caused squamous, cuboidal and goblet cell dysplasia in intrapulmonary conducting airways. Atypical epithelial cells that stained for proSP-C, and had morphological characteristics of alveolar type II cells, were observed in bronchioles of the transgenic mice. Catnb{Delta}(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 {beta}-catenin negatively regulated the expression of the Foxa2 promoter. Catnb{Delta}(ex3) also caused pulmonary tumors in adult mice. Activation of {beta}-catenin caused ectopic differentiation of alveolar type II-like cells in conducting airways, goblet cell hyperplasia, and airspace enlargement, demonstrating a critical role for the Wnt-{beta}-catenin signal transduction pathway in the differentiation of the respiratory epithelium in the postnatal lung.




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