期刊
DEVELOPMENTAL DYNAMICS
卷 241, 期 5, 页码 911-923出版社
WILEY-BLACKWELL
DOI: 10.1002/dvdy.23773
关键词
airway epithelium; Clara cells; gene regulation; lung development; transcription factors
资金
- American Thoracic Society [ATS-06-035]
- Swedish Research Council, medicine [14677, 14678, 14794]
- Swedish Heart-Lung Foundation [20050443]
- Jeansson, Foundation
- Ake Wiberg, Foundation
- Magnus Bergvall, Foundation
- Konsul Th C Bergh Research Foundation
- General Maternity Hospital Foundation
- Karolinska Institutet
Background: CCAAT/enhancer-binding protein (C/EBP)a is crucial for lung development and differentiation of the pulmonary epithelium. Conversely, no lung defects have been observed in C/EBP beta-deficient mice, although C/EBP beta trans-activate pulmonary genes by binding to virtually identical DNA-sequences as C/EBPa. Thus, the pulmonary phenotype of mice lacking C/EBP beta could be explained by functional replacement with C/EBPa. We investigated whether C/EBPa and C/EBP beta have overlapping functions in regulating lung epithelial differentiation during organogenesis. Epithelial differentiation was assessed in mice with a lung epithelialspecific (SFTPC-Cre-mediated) deletion of C/EBPa (Cebpa?LE), C/EBP beta (Cebpb?LE), or both genes (Cebpa?LE; Cebpb?LE). Results: Both Cebpa?LE mice and Cebpa?LE; Cebpb?LE mice demonstrated severe pulmonary immaturity compared to wild-type littermates, while no differences in lung histology or epithelial differentiation were observed in Cebpb?LE mice. In contrast to Cebpa?LE mice, Cebpa?LE; Cebpb?LE mice also displayed undifferentiated Clara cells with markedly impaired protein and mRNA expression of Clara cell secretory protein (SCGB1A1), compared to wild-type littermates. In addition, ectopic mucus-producing cells were observed in the conducting airways of Cebpa?LE; Cebpb?LE mice. Conclusions: Our findings demonstrate that C/EBPa and C/EBP beta play pivotal, and partly overlapping roles in determining airway epithelial differentiation, with possible implications for tissue regeneration in lung homeostasis and disease. Developmental Dynamics 241:911923, 2012. (c) 2012 Wiley Periodicals, Inc.
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