Compensatory roles of Foxa1 and Foxa2 during lung morphogenesis.
Foxa1 and Foxa2 are closely related family members of the Foxa group of transcription factors that are coexpressed in subsets of respiratory epithelial cells throughout lung morphogenesis. Shared patterns of expression, conservation of DNA binding, and transcriptional activation domains indicate that they may serve complementary functions in the regulation of gene expression during lung morphogenesis. Whereas branching morphogenesis of the fetal lung occurs normally in the Foxa2Delta/Delta and Foxa1-/- mice, deletion of both Foxa1 and Foxa2 (in Foxa2Delta/Delta, Foxa1-/- mice) inhibited cell proliferation, epithelial cell differentiation, and branching. Dilation of terminal lung tubules and decreased branching were observed as early as embryonic day 12.5. Foxa1 and Foxa2 regulated Shh (sonic hedgehog) and Shh-dependent genes in the respiratory epithelial cells that influenced the expression of genes in the pulmonary mesenchyme that are required for branching morphogenesis. Epithelial cell differentiation, as indicated by lack of expression of surfactant protein B, surfactant protein C, the Clara cell secretory protein, and Foxj1, was inhibited. Foxa family members regulate signaling and transcriptional programs required for morphogenesis and cell differentiation during formation of the lung.
Wan
Huajing
H
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA.
Dingle
Sharon
S
Xu
Yan
Y
Besnard
Valérie
V
Kaestner
Klaus H
KH
Ang
Siew-Lan
SL
Wert
Susan
S
Stahlman
Mildred T
MT
Whitsett
Jeffrey A
JA
D000199:Actins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000502:physiology / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000378:metabolism; D053823:Hedgehog Proteins; D051541:Hepatocyte Nuclear Factor 3-alpha; D051542:Hepatocyte Nuclear Factor 3-beta; D008168:Lung / Q000033:anatomy & histology / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000196:embryology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins
D000199:Actins; D004268:DNA-Binding Proteins; C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; D006023:Glycoproteins; D053823:Hedgehog Proteins; D051541:Hepatocyte Nuclear Factor 3-alpha; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C465570:Shh protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; C095937:Wnt7b protein, mouse; D051542:Hepatocyte Nuclear Factor 3-beta