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Molecular and Cellular Biology, February 2006, p. 1109-1123, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.1109-1123.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Respiratory Failure Due to Differentiation Arrest and Expansion of Alveolar Cells following Lung-Specific Loss of the Transcription Factor C/EBP in Mice^¶

Daniela S. Bassères ,^1,, Elena Levantini,^1, Hongbin Ji,² Stefano Monti,³ Shannon Elf,¹ Tajhal Dayaram,¹ Maris Fenyus,¹ Olivier Kocher,¹ Todd Golub,³ Kwok-kin Wong,² Balazs Halmos,^1, and Daniel G. Tenen^1*

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts,¹ Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts,² Broad Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts³

Received 23 August 2005/ Returned for modification 12 October 2005/ Accepted 14 November 2005

The leucine zipper family transcription factor CCAAT enhancer binding protein alpha (C/EBP) inhibits proliferation and promotes differentiation in various cell types. In this study, we show, using a lung-specific conditional mouse model of C/EBP deletion, that loss of C/EBP in the respiratory epithelium leads to respiratory failure at birth due to an arrest in the type II alveolar cell differentiation program. This differentiation arrest results in the lack of type I alveolar cells and differentiated surfactant-secreting type II alveolar cells. In addition to showing a block in type II cell differentiation, the neonatal lungs display increased numbers of proliferating cells and decreased numbers of apoptotic cells, leading to epithelial expansion and loss of airspace. Consistent with the phenotype observed, genes associated with alveolar maturation, survival, and proliferation were differentially expressed. Taken together, these results identify C/EBP as a master regulator of airway epithelial maturation and suggest that the loss of C/EBP could also be an important event in the multistep process of lung tumorigenesis. Furthermore, this study indicates that exploring the C/EBP pathway might have therapeutic benefits for patients with respiratory distress syndromes.

^¶ Supplemental material for this article may be found at http://mcb.asm.org/.

D. S. Bassères and E. Levantini contributed equally to this work.

Present address: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, N.C.

Present address: Ireland Cancer Center, Case Western Reserve University, Cleveland, Ohio.

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