title: Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ.
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.
authors.affiliation: Department of Medicine, Respiratory Medicine Unit, Karolinska Institutet, Stockholm, Sweden. abraham.roos@ki.se
authors.forename: Abraham B
authors.initials: AB
authors.lastname: Roos
authors.forename: Tove
authors.initials: T
authors.lastname: Berg
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Barton
authors.forename: Lukas
authors.initials: L
authors.lastname: Didon
authors.forename: Magnus
authors.initials: M
authors.lastname: Nord
mesh_terms: D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008168:Lung / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D038081:Organogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014598:Uteroglobin / Q000235:genetics / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; C556390:Scgb1a1 protein, mouse; D014598:Uteroglobin