The Role of Nfib in Lung Development
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In vertebrates, the Nuclear factor I (NFI) transcription factor family consists of four genes ( Nfia, Nfib, Nfic and Nfix ) that regulate the development of multiple organs. During lung development, Nfib is expressed predominantly in mesenchyme at E14.5 and E16.5 and in both mesenchyme and epithelium at E18.5. Mice lacking Nfib have severe lung maturation defects and die at birth. I show here that at E18.5 there are more PCNA, BrdU, PHH3 and Ki67 positive cells in Nfib -/- lungs than in wild type lungs. Much of the additional Ki67 and PCNA staining is in TTF-1 + epithelial cells. I show by RT-QPCR and immunostaining that loss of Nfib decreases the expression of markers of alveolar epithelial cells ( Aqp5 & Sfpc ) and Clara cells ( Scgb1a1 ) in E18.5 lungs. To test whether the loss of Nfib in mesenchyme only affects lung development, Nfib flox/flox , Dermo1-Cre mice were analyzed. Loss of Nfib in mesenchyme results in decreased Aqp5 & Sfpc expression, increased proliferation marker expression, defects in lung vasculature and in sacculation similar to that seen in Nfib -/- mice. In contrast, there is no significant difference between Nfib flox/flox , Dermo1-Cre and Nfib flox/flox lungs in the expression of Scgb1a1 . No defect in lung sacculation or lung vascular development was found in Nfib flox/flox , Tek-Cre mice. Microarray and RT-QPCR data indicate that the loss of Nfib in lung mesenchyme affects the expression of genes associated with extracellular matrix, cell adhesion and FGF signaling which could affect lung maturation. I conclude that Nfib expression in lung mesenchyme regulates both mesenchymal and epithelial cell proliferation, and is required for the differentiation of specific epithelial cell types and lung vascular development during lung maturation.