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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism
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Animals
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Calcineurin / genetics*
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Calcineurin / metabolism
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Cell Line, Transformed
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Gene Expression Profiling
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Gene Expression Regulation, Developmental / genetics
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Hepatocyte Nuclear Factor 3-alpha / genetics
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Hepatocyte Nuclear Factor 3-alpha / metabolism
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Hepatocyte Nuclear Factor 3-beta / genetics
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Hepatocyte Nuclear Factor 3-beta / metabolism
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Lung / embryology
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Lung / metabolism*
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Lung / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Models, Biological
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NFATC Transcription Factors / genetics
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NFATC Transcription Factors / metabolism*
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Nuclear Proteins / genetics
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Oligonucleotide Array Sequence Analysis
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Pulmonary Surfactant-Associated Proteins / genetics
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Pulmonary Surfactant-Associated Proteins / metabolism
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Respiratory Insufficiency / genetics
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Respiratory Insufficiency / pathology
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Respiratory Mucosa / metabolism
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Signal Transduction / physiology*
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Thyroid Nuclear Factor 1
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Transcription Factors / genetics
Substances
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ATP-Binding Cassette Transporters
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Abca3 protein, mouse
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DNA-Binding Proteins
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Foxa1 protein, mouse
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Foxa2 protein, mouse
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Hepatocyte Nuclear Factor 3-alpha
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NFATC Transcription Factors
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Nfatc3 protein, mouse
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Nuclear Proteins
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Pulmonary Surfactant-Associated Proteins
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Thyroid Nuclear Factor 1
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Transcription Factors
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Ttf1 protein, mouse
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Hepatocyte Nuclear Factor 3-beta
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Calcineurin