Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ.

Background: CCAAT/enhancer-binding protein (C/EBP)α is crucial for lung development and differentiation of the pulmonary epithelium. Conversely, no lung defects have been observed in C/EBPβ-deficient mice, although C/EBPβ trans-activate pulmonary genes by binding to virtually identical DNA-sequences as C/EBPα. Thus, the pulmonary phenotype of mice lacking C/EBPβ could be explained by functional replacement with C/EBPα. We investigated whether C/EBPα and C/EBPβ have overlapping functions in regulating lung epithelial differentiation during organogenesis. Epithelial differentiation was assessed in mice with a lung epithelial-specific (SFTPC-Cre-mediated) deletion of C/EBPα (Cebpa(ΔLE) ), C/EBPβ (Cebpb(ΔLE) ), or both genes (Cebpa(ΔLE) ; Cebpb(ΔLE) ).

Results: Both Cebpa(ΔLE) mice and Cebpa(ΔLE) ; Cebpb(ΔLE) mice demonstrated severe pulmonary immaturity compared to wild-type littermates, while no differences in lung histology or epithelial differentiation were observed in Cebpb(ΔLE) mice. In contrast to Cebpa(ΔLE) mice, Cebpa(ΔLE) ; Cebpb(ΔLE) 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(ΔLE) ; Cebpb(ΔLE) mice.

Conclusions: Our findings demonstrate that C/EBPα and C/EBPβ play pivotal, and partly overlapping roles in determining airway epithelial differentiation, with possible implications for tissue regeneration in lung homeostasis and disease.