Cited2 is required for fetal lung maturation.
ABSTRACT Lung maturation at the terminal sac stage of lung development is characterized by a coordinated increase in terminal sac formation and vascular development in conjunction with the differentiation of alveolar type I and type II epithelial cells. The Cited2-Tcfap2a/c complex has been shown to activate transcription of Erbb3 and Pitx2c during mouse development. In this study, we show that E17.5 to E18.5 Cited2-null lungs had significantly reduced terminal sac space due to an altered differentiation of type I and type II alveolar epithelial cells. In addition, E17 Cited2-null lungs exhibited a decrease in the number of apoptotic cells, contributing to the loss in airspace. Consistent with the phenotype, genes associated with alveolar cell differentiation and survival were differentially expressed in Cited2-null fetal lungs compared to those of wild-type littermates. Moreover, expression of Cebpa, a key regulator of airway epithelial maturation, was significantly decreased in Cited2-null fetal lungs. Cited2 and Tcfap2c were present on the Cebpa promoter in E18.5 lungs to activate Cebpa transcription. We propose that the Cited2-Tcfap2c complex controls lung maturation by regulating Cebpa expression. Understanding the function of this complex may provide novel therapeutic strategies for patients with respiratory distress syndromes.
Article: Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme.[show abstract] [hide abstract]
ABSTRACT: Mammalian lung develops as an evagination of ventral gut endoderm into the underlying mesenchyme. Iterative epithelial branching, regulated by the surrounding mesenchyme, generates an elaborate network of airways from the initial lung bud. Fibroblast growth factors (FGFs) often mediate epithelial-mesenchymal interactions and mesenchymal Fgf10 is essential for epithelial branching in the developing lung. However, no FGF has been shown to regulate lung mesenchyme. In embryonic lung, Fgf9 is detected in airway epithelium and visceral pleura at E10.5, but is restricted to the pleura by E12.5. We report that mice homozygous for a targeted disruption of Fgf9 exhibit lung hypoplasia and early postnatal death. Fgf9(-/-) lungs exhibit reduced mesenchyme and decreased branching of airways, but show significant distal airspace formation and pneumocyte differentiation. Our results suggest that Fgf9 affects lung size by stimulating mesenchymal proliferation. The reduction in the amount of mesenchyme in Fgf9(-/-) lungs limits expression of mesenchymal Fgf10. We suggest a model whereby FGF9 signaling from the epithelium and reciprocal FGF10 signaling from the mesenchyme coordinately regulate epithelial airway branching and organ size during lung embryogenesis.Development 07/2001; 128(11):2095-106. · 6.60 Impact Factor
Article: X-Ray diffraction studies of fibrillin-rich microfibrils: effects of tissue extension on axial and lateral packing.[show abstract] [hide abstract]
ABSTRACT: X-ray diffraction of hydrated fibrillin rich microfibrils, in the form of zonular filaments from bovine eyes, demonstrated meridional diffraction peaks indexing on a fundamental periodicity of approximately 56 nm in the relaxed state. The effect of sample extensions of up to 50% in length produced an increase in the axial periodicity of only 4% as judged by alteration of the diffraction peak position of the third meridional order. This effect was shown to be reversible. Further extension to 100% of the tissue rest length caused extensive deterioration in the quality of the diffraction and resulted in a more complex meridional diffraction series, where the fundamental axial periodicity also changed to a length of approximately 80 nm. The fibrillin diffraction image also contains an equatorial diffraction peak that is enhanced upon tissue extension. The measurement of the molecular spacing from the equatorial diffraction profile indicated that the closest approach of molecules gave a broad interference peak of spacing 28 nm, this is nearly twice the molecular diameter as estimated from electron microscopy of dehydrated samples.Journal of Structural Biology 02/1998; 122(1-2):123-7. · 3.41 Impact Factor