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Calcineurin/Nfat signaling is required for perinatal lung maturation and function
Vrushank Davé, … , Gerald R. Crabtree, Jeffrey A. Whitsett
Vrushank Davé, … , Gerald R. Crabtree, Jeffrey A. Whitsett
Published October 2, 2006
Citation Information: J Clin Invest. 2006;116(10):2597-2609. https://doi.org/10.1172/JCI27331.
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Research Article Pulmonology

Calcineurin/Nfat signaling is required for perinatal lung maturation and function

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Abstract

Pulmonary surfactant proteins and lipids are required for lung function after birth. Lung immaturity and resultant surfactant deficiency cause respiratory distress syndrome, a common disorder contributing to morbidity and mortality in preterm infants. Surfactant synthesis increases prior to birth in association with formation of the alveoli that mediate efficient gas exchange. To identify mechanisms controlling perinatal lung maturation, the Calcineurin b1 (Cnb1) gene was deleted in the respiratory epithelium of the fetal mouse. Deletion of Cnb1 caused respiratory failure after birth and inhibited the structural maturation of the peripheral lung. Synthesis of surfactant and a lamellar body–associated protein, ABC transporter A3 (ABCA3), was decreased prior to birth. Nuclear factor of activated T cells (Nfat) calcineurin-dependent 3 (Nfatc3), a transcription factor modulated by calcineurin, was identified as a direct activator of Sftpa, Sftpb, Sftpc, Abca3, Foxa1, and Foxa2 genes. The calcineurin/Nfat pathway controls the morphologic maturation of lungs prior to birth and regulates expression of genes involved in surfactant homeostasis that are critical for adaptation to air breathing.

Authors

Vrushank Davé, Tawanna Childs, Yan Xu, Machiko Ikegami, Valérie Besnard, Yutaka Maeda, Susan E. Wert, Joel R. Neilson, Gerald R. Crabtree, Jeffrey A. Whitsett

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Figure 1

Components of the Cn/Nfat pathway during lung development.

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Components of the Cn/Nfat pathway during lung development.
Immunostainin...
Immunostaining of CnA, CnB1, and its effector Nfatc3 in fetal mouse lungs from E11.5 to E18.5. (A) CnA was restricted to epithelial cells of the lung buds at E11.5. (D) At E14.5 CnA was detected in apical-basal membranes of the epithelial cells. (G and J) At E17.5–E18.5, CnA was expressed in both the epithelium and the mesenchyme. (B and E) CnB1 was detected in apical-basal regions of epithelial cells at E11.5 and E14.5, with intense staining in the peripheral lung tubules at E14.5. (H and K) At E17.5–E18.5, CnB1 was detected in both the mesenchyme and the epithelium. (C and F) Nfatc3 was detected in apical membranes of respiratory epithelial cells and mesenchyme at E11.5 and E14.5. (I and L) Nuclear Nfatc3 staining was observed in epithelial, endothelial, and mesenchymal cells at E17.5 and E18.5. Scale bars: 100 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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