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 (CebpaΔLE), C/EBPβ (CebpbΔLE), or both genes (CebpaΔLE; CebpbΔLE). Results: Both CebpaΔLE mice and CebpaΔLE; CebpbΔLE mice demonstrated severe pulmonary immaturity compared to wild‐type littermates, while no differences in lung histology or epithelial differentiation were observed in CebpbΔLE mice. In contrast to CebpaΔLE mice, CebpaΔLE; CebpbΔLE 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 CebpaΔLE; CebpbΔLE 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. Developmental Dynamics 241:911–923, 2012. © 2012 Wiley Periodicals, Inc.

Generation of multiciliated cells in functional airway epithelia from human induced pluripotent stem cells

“…Zero, 5, and 20 ng/mL were used, and RNA was collected from the differentiation at day 45. Analysis of lungrelated gene expression at this time point showed that 5 ng/mL supported the most robust up-regulation of genes related to lung development and mature lung cells, such as DE makers FOXA2, GATA6, goblet cell marker MUC5A/C, MUC1, CFTR, and transcription factor cEBPα (important for lung-branching morphogenesis) (33,34), and was thus used as the working concentration for the protocol (shown in SI Appendix, Fig. S7).…”

Lung epithelial tip progenitors integrate glucocorticoid- and STAT3-mediated signals to control progeny fate

“…1B). A recent report has suggested that CEBPA functions redundantly with CEBPB to promote airway differentiation (Roos et al, 2012). We hypothesize that the airway CEBPA staining we observe reflects a second site of expression and therefore do not use this protein as a specific marker of developing alveolar fate.…”

Genome-wide interaction study of dust mite allergen on lung function in children with asthma

“…IL-17 has been amply implicated in the pathogenesis of asthma 40–42 , and studies in dust-mite sensitized subjects have shown that specific immunotherapy can lead to reductions in IL-17 levels that correlate with symptom reduction 43 . However, CEBPβ also participates in several other pathways, including IL-4, IL-6, TNFα and IFN-γ signaling pathways, and it has been implicated in airway epithelium differentiation during lung development 44 . Thus, functional studies will be needed to determine the precise role of CEBPβ in the interaction between dust mite and genotype on lung function in asthma.…”