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

Dev Dyn. 2012 May;241(5):911-23. doi: 10.1002/dvdy.23773. Epub 2012 Mar 23.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-alpha / genetics
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism*
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • Cell Differentiation / physiology*
  • Gene Expression Regulation, Developmental
  • Humans
  • Lung / embryology*
  • Lung / metabolism
  • Mice
  • Organogenesis / physiology*
  • Signal Transduction / physiology
  • Uteroglobin / genetics
  • Uteroglobin / metabolism

Substances

  • CCAAT-Enhancer-Binding Protein-alpha
  • CCAAT-Enhancer-Binding Protein-beta
  • Scgb1a1 protein, mouse
  • Uteroglobin