Defects in pulmonary vasculature and perinatal lung hemorrhage in mice heterozygous null for the Forkhead Box f1 transcription factor

Decreased pulmonary expression of Forkhead Box f1 (Foxf1) transcription fac tor was associated with lethal alveolar hemorrhage in 55% of the Foxf1 +/- newborn mice. The severity of the pulmonary abnormalities correlates with t he levels of Foxf1 mRNA, Defects in alveolarization and vasculogenesis were observed in subsets of the Foxf1 +/- mice with relatively low levels of ex pression from the normal Foxf1 allele, Lung hemorrhage was coincident with disruption of the mesenchymal-epithelial cell interfaces in the alveolar an d bronchiolar regions of the lung parenchyma and was associated with increa sed apoptosis and reduced surfactant protein B (SP-B) expression. Finally, the lung defect associated with the Foxf1 +/- mutation was accompanied by r educed expression of vascular endothelial growth factor (VEGF), the VEGF re ceptor 2 (Flk-1), bone morphogenetic protein 4 (Bmp-4), and the transcripti on factors of the Brachyury T-Box family (Tbx2-Tbx5) and Lung Kruppel-like Factor. Reduction in the level of Foxf1 caused neonatal pulmonary hemorrhag e and abnormalities in alveologenesis, implicating this transcription facto r in the regulation of mesenchyme-epithelial interaction critical for lung morphogenesis. (C) 2001 Academic Press