Calcineurin/Nfat signaling is required for perinatal lung maturation and function.
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.
Davé
Vrushank
V
Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA. davev0@cchmc.org
Childs
Tawanna
T
Xu
Yan
Y
Ikegami
Machiko
M
Besnard
Valérie
V
Maeda
Yutaka
Y
Wert
Susan E
SE
Neilson
Joel R
JR
Crabtree
Gerald R
GR
Whitsett
Jeffrey A
JA
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019703:Calcineurin / Q000235:genetics* / Q000378:metabolism; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D037661:Pulmonary Surfactant-Associated Proteins / Q000235:genetics / Q000378:metabolism; D012131:Respiratory Insufficiency / Q000235:genetics / Q000473:pathology; D020545:Respiratory Mucosa / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; C512026:Abca3 protein, mouse; D004268:DNA-Binding Proteins; C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; D009687:Nuclear Proteins; D037661:Pulmonary Surfactant-Associated Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; C504004:Ttf1 protein, mouse; D051542:Hepatocyte Nuclear Factor 3-beta; D019703:Calcineurin