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

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 8

Regulation of Cnb1 and its participation with TTF-1 in a transcriptional network during lung formation.

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Regulation of Cnb1 and its participation with TTF-1 in a transcriptional...
(A) Consensus TTF-1 and Nfat sites were detected in the Cnb1 proximal promoter. Black and white boxes represent Nfat sites (GGAAA and AGAAA, respectively); black circles represent TTF-1 sites. (B) The Cnb1 gene promoter was activated by TTF-1 and Nfatc3. Cotransfection of TTF-1 expression vector (0, 0.25, 0.5, and 1 μg) with a fixed amount of Cnb1-755-luc (0.25 μg; a promoter-reporter construct containing –755 bps of 5′-upstream regulatory sequence of mouse Cnb1 gene cloned into XhoI and HindIII site of pGL3 basic plasmid) increased luciferase activity in HeLa and MLE-15 cells. TTF-1 (0.5 μg) and Nfatc3 (0.5 μg) synergistically activated the Cnb1 gene promoter in HeLa cells. (C) Proposed network of transcription factors — regulated by or interacting with the Cn/Nfat pathway — directing perinatal lung maturation. This maturation process begins in the saccular stage from E17 to postnatal day 5 (PND-5) and is completed at the end of the alveolar stage by PND-21 in mice. TTF-1 regulates CnB1 expression. CnB1 dephosphorylates and activates Nfatc3 (red dashed arrow). In turn, Nfatc3 (a) activates Foxa1 and Foxa2; (b) synergistically interacts with TTF-1 to activate surfactant protein genes and Abca3; and (c) increases transcription of CnA required for its own activity (61). Foxa1, Foxa2, and TTF-1 are known to activate a number of shared target genes critical for lung function (blue arrows). Cn may also function via Nfat-independent pathways (dashed arrow).