Airway epithelial cell differentiation during lung organogenesis requires C/EBPa and C/EBP ss

作者：Roos Abraham B^*; Berg Tove; Barton Jenny L; Didon Lukas; Nord Magnus

来源：Developmental Dynamics, 2012, 241(5): 911-923.

DOI：10.1002/dvdy.23773

• airway epithelium
• Clara cells
• gene regulation
• lung development
• transcription factors

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.

• 出版日期2012-5