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Ectopic expression of C/EBP in the lung epithelium disrupts late lung development

Division for Respiratory Medicine, Department of Medicine, Karolinska Institute, Lung Research Laboratory, Karolinska University Hospital-Solna, Stockholm, Sweden

Submitted 28 November 2005 ; accepted in final form 7 May 2006

The lung develops from the endoderm through a process of branching morphogenesis. This process is highly active during the pseudoglandular stage of lung development and continues into the canalicular stage, resulting in the formation of terminal sacs. CCAAT/enhancer binding proteins (C/EBPs) are transcription factors regulating central aspects of differentiation and proliferation. We report here the developmental expression of C/EBP, -, and - in the lung. C/EBP exhibits a dynamic expression pattern and is first detected during the late pseudoglandular stage. At this stage, expression is observed in a subset of epithelial cells in the distal parts of the branching tubules. The expression of C/EBP is confined to nonproliferating cells. To examine the role of C/EBP in lung development, we generated transgenic mice ectopically expressing C/EBP in the lung epithelium using the human surfactant protein C promoter. Lungs from these mice were of normal size but exhibited a phenotype characterized by fewer and larger developing epithelial tubules, indicating that the branching process was affected. No effects on overall proliferation or cellular differentiation were observed. When this phenotype was compared with that of mice carrying a targeted mutation of the Cebpa gene, the Cebpa^–/– mice exhibited a similar developmental phenotype. In conclusion, our results show a role for C/EBP in lung development and suggest a function in the later stages of lung branching morphogenesis.

CCAAT/enhancer binding proteins; transcription factors; expression pattern; branching morphogenesis; cellular differentiation

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