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J. Biol. Chem., Vol. 280, Issue 14, 13809-13816, April 8, 2005

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Compensatory Roles of Foxa1 and Foxa2 during Lung Morphogenesis^*

Huajing Wan, Sharon Dingle, Yan Xu, Valérie Besnard, Klaus H. Kaestner, Siew-Lan Ang¶, Susan Wert, Mildred T. Stahlman||, and Jeffrey A. Whitsett**

From the Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, the Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6145, the ^¶National Institute for Medical Research, Division of Developmental Neurobiology, London NW7 1AA, United Kingdom, and the ^||Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2370

Foxa1 and Foxa2 are closely related family members of the Foxa group of transcription factors that are coexpressed in subsets of respiratory epithelial cells throughout lung morphogenesis. Shared patterns of expression, conservation of DNA binding, and transcriptional activation domains indicate that they may serve complementary functions in the regulation of gene expression during lung morphogenesis. Whereas branching morphogenesis of the fetal lung occurs normally in the Foxa2^/ and Foxa1^–/– mice, deletion of both Foxa1 and Foxa2 (in Foxa2^/, Foxa1^–/– mice) inhibited cell proliferation, epithelial cell differentiation, and branching. Dilation of terminal lung tubules and decreased branching were observed as early as embryonic day 12.5. Foxa1 and Foxa2 regulated Shh (sonic hedgehog) and Shh-dependent genes in the respiratory epithelial cells that influenced the expression of genes in the pulmonary mesenchyme that are required for branching morphogenesis. Epithelial cell differentiation, as indicated by lack of expression of surfactant protein B, surfactant protein C, the Clara cell secretory protein, and Foxj1, was inhibited. Foxa family members regulate signaling and transcriptional programs required for morphogenesis and cell differentiation during formation of the lung.

Received for publication, December 15, 2004 , and in revised form, January 14, 2005.

^* This work was supported by National Institutes of Health Grants HL56387, HL75770, and HL38859. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2 showing PECAM immunohistochemistry and phosphohistone H3 staining, respectively, of Foxa1^–/–/Foxa2^/.

^** To whom correspondence should be addressed: Cincinnati Children's Hospital Medical Center, Divisions of Neonatology and Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039. Tel.: 513-636-4830; Fax: 513-636-7868; E-mail: jeff.whitsett{at}cchmc.org.

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