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J. Biol. Chem., Vol. 278, Issue 41, 40231-40238, October 10, 2003
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-Catenin Is Required for Specification of Proximal/Distal Cell Fate during Lung Morphogenesis*





From the
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, the ¶Max-Delbrueck Center for Molecular Medicine, Berlin 13125, Germany, and the ||Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
The lungs are divided, both structurally and functionally, into two distinct components, the proximal airways, which conduct air, and the peripheral airways, which mediate gas exchange. The mechanisms that control the specification of these two structures during lung development are currently unknown. Here we show that
-catenin signaling is required for the formation of the distal, but not the proximal, airways. When the gene for
-catenin was conditionally excised in epithelial cells of the developing mouse lung prior to embryonic day 14.5, the proximal lung tubules grew and differentiated appropriately. The mice, however, died at birth because of respiratory failure. Analysis of the lungs by in situ hybridization and immunohistochemistry, using molecular markers of the epithelial and mesenchymal components of both proximal and peripheral airways, showed that the lungs were composed primarily of proximal airways. These observations establish, for the first time, both the sites and timing of specification of the proximal and peripheral airways in the developing lung, and that
-catenin is one of the essential components of this specification.
Received for publication, June 4, 2003 , and in revised form, July 24, 2003.
* This work was supported by National Institutes of Health Grant HL56387 (to J. A. W. and S. E. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039. Tel.: 513-636-3456; Fax: 513-636-7868; E-mail: michael.mucenski{at}cchmc.org.
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