CRITICAL ROLES OF FORKHEAD BOX A2 DURING LUNG DEVELOPMENT
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 the targeted mutagenesis of Foxa2 gene in mice is lethal before formation of the lung, its potential roles in lung morphogenesis and homeostasis has not been determined. In order to discern the role of Foxa2 in epithelial cell differentiation and pulmonary adaptation at birth, triple transgenic mice (Foxa2Flx/Flx, SPC-rtTA, (TetO)7-cre and Foxa2Flx/Flx, CCSP-rtTA, (TetO)7-cre) were generated in which Foxa2 was selectively deleted in the respiratory epithelial cells of the developing lung. Although lobulation and early branching morphogenesis were normal, decreased lung to body ratio, arrested epithelial cell differentiation and abnormalities in syntheses of surfactant proteins and lipids were observed prior to birth. When observed during normal delivery (E19.5-20), approximately 50% of the Foxa2 delta/delta mice developed respiratory failure within 2-3 hours after birth. Histologic examination of the pups found in distress or moribund, revealed atelectasis, with extensive formation of hyaline membranes lining terminal airways, typical of findings in preterm infants with RDS. Goblet cell hyperplasia, mucin production, inflammation and airspace abnormalities were observed in Foxa2 delta/delta; mice postnatally and all of the Foxa2 delta/delta mice will die before PN60. Morphological, biochemical and functional analysis of the Foxa2 delta/delta mice indicated that Foxa2 is the first gene shown to regulate the complex program of pulmonary maturation required for transition to air breathing at birth and normal lung function after birth through direct and indirect transcriptional regulation of genes mediating surfactant homeostasis and host defense. Foxa1 and Foxa2 are co-expressed in subsets of respiratory epithelial cells during lung morphogenesis. Similarity of the expression patterns and conservation of their DNA binding domains indicate that they may share overlapping functions during development. Deletion of both Foxa1 and Foxa2 disrupted lung branching morphogenesis and epithelial cell differentiation, indicating that Foxa1 and Foxa2 play overlapping roles in the process of branching morphogenesis and epithelial cell differentiation of the lung.
School:University of Cincinnati
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:lung forkhead winged helix transcription factor development pulmonary epithelium surfactant
Date of Publication:01/01/2004