1. Defects in pulmonary vasculature and perinatal lung hemorrhage in mice heterozygous null for the Forkhead Box f1 transcription factor.
- Author
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Kalinichenko VV, Lim L, Stolz DB, Shin B, Rausa FM, Clark J, Whitsett JA, Watkins SC, and Costa RH
- Subjects
- Alleles, Animals, Apoptosis, Blotting, Western, Bone Morphogenetic Protein 4, Bone Morphogenetic Proteins metabolism, DNA, Complementary metabolism, Dose-Response Relationship, Drug, Endothelial Growth Factors metabolism, Endothelium metabolism, Forkhead Transcription Factors, Hemorrhage, Heterozygote, Immunohistochemistry, In Situ Nick-End Labeling, Lung pathology, Lymphokines metabolism, Mice, Mice, Knockout, Microscopy, Electron, Models, Genetic, Mutation, Oligonucleotide Array Sequence Analysis, Phenotype, Platelet Endothelial Cell Adhesion Molecule-1 metabolism, RNA, Messenger metabolism, Receptor Protein-Tyrosine Kinases metabolism, Receptors, Growth Factor metabolism, Receptors, Vascular Endothelial Growth Factor, Trans-Activators metabolism, Transcription Factors physiology, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, beta-Galactosidase metabolism, DNA-Binding Proteins, Lung embryology, Lung metabolism, Transcription Factors biosynthesis, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
Decreased pulmonary expression of Forkhead Box f1 (Foxf1) transcription factor was associated with lethal alveolar hemorrhage in 55% of the Foxf1 +/- newborn mice. The severity of the pulmonary abnormalities correlates with the levels of Foxf1 mRNA. Defects in alveolarization and vasculogenesis were observed in subsets of the Foxf1 +/- mice with relatively low levels of expression from the normal Foxf1 allele. Lung hemorrhage was coincident with disruption of the mesenchymal-epithelial cell interfaces in the alveolar and bronchiolar regions of the lung parenchyma and was associated with increased apoptosis and reduced surfactant protein B (SP-B) expression. Finally, the lung defect associated with the Foxf1 +/- mutation was accompanied by reduced expression of vascular endothelial growth factor (VEGF), the VEGF receptor 2 (Flk-1), bone morphogenetic protein 4 (Bmp-4), and the transcription factors of the Brachyury T-Box family (Tbx2-Tbx5) and Lung Kruppel-like Factor. Reduction in the level of Foxf1 caused neonatal pulmonary hemorrhage and abnormalities in alveologenesis, implicating this transcription factor in the regulation of mesenchyme-epithelial interaction critical for lung morphogenesis., (Copyright 2001 Academic Press.)
- Published
- 2001
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