Foxa2 regulates alveolarization and goblet cell hyperplasia

Abstract

The airways are lined by several distinct epithelial cells that play unique roles in pulmonary homeostasis; however, the mechanisms controlling their differentiation in health and disease are poorly understood. The winged helix transcription factor, FOXA2, is expressed in the foregut endoderm and in subsets of respiratory epithelial cells in the fetal and adult lung. Because targeted mutagenesis of the Foxa2 gene in mice is lethal before formation of the lung, its potential role in lung morphogenesis and homeostasis has not been determined. We selectively deleted Foxa2 in respiratory epithelial cells in the developing mouse lung. Airspace enlargement, goblet cell hyperplasia, increased mucin and neutrophilic infiltration were observed in lungs of the Foxa2-deleted mice. Experimental goblet cell hyperplasia caused by ovalbumin sensitization,interleukin 4 (IL4), IL13 and targeted deletion of the gene encoding surfactant protein C (SP-C), was associated with either absent or decreased expression of Foxa2 in airway epithelial cells. Analysis of lung tissue from patients with a variety of pulmonary diseases revealed a strong inverse correlation between FOXA2 and goblet cell hyperplasia. FOXA2 is required for alveolarization and regulates airway epithelial cell differentiation in the postnatal lung.

Differential expression of chitinases identify subsets of murine airway epithelial cells in allergic inflammation

“…Finally, it appears that the vast majority of the in vitro work done with murine and human airway cell lines show induction of mucus in response to IL-13 ( 1, 7, 11, 25, 26). The results here suggest that these cell lines are representative of proximal but not distal Since Foxa2 had previously been reported to be downregulated by IL-13 in airway epithelial cells and this downregulation was proposed to be important in induction of mucus in those cells (50), we examined the AMCase-expressing cells to determine their Foxa2 status. We confirmed the observation that Foxa2 is downregulated in proximal cells while noting that Foxa2 expression is retained distally.…”

“…However, IL-13 signaling in airway epithelial cells has previously been reported to downregulate expression of Foxa2, a member of the forkhead transcription factor family (50). This downregulation of Foxa2 has been reported to lead to mucus production (50). We wondered therefore whether Foxa2 downregulation was occurring in all airway epithelial cells, including AMCaseproducing cells, or was limited to the proximal mucus produc- ing cells.…”

“…Thus IL-13 signaling is clearly taking place in the AMCase-producing distal cells. However, IL-13 signaling in airway epithelial cells has previously been reported to downregulate expression of Foxa2, a member of the forkhead transcription factor family (50). This downregulation of Foxa2 has been reported to lead to mucus production (50).…”

Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease

“…FOXA1 contributes to pancreatic beta-cell function 32 and both regulate signaling and transcriptional programs required for morphogenesis and goblet cell differentiation during formation. 33,34 There is a binding site for Hepatic Nuclear Factor 1 (HNF1) in the AGR2 promoter region at SNP 07AGRNP53. HNF1 and FOXA1 and FOXA2 belong to the same family.…”

Regulation of Airway Mucin Gene Expression

“…Conditional knockout of the Foxa2 gene in mice leads to impaired alveolarization and goblet cell hyperplasia. Mucous cell differentiation and upregulation of Muc5ac lead to the downregulation of Foxa2 (114). IL-13 and EGFR signaling can also downregulate Foxa2.…”