title: BMP signaling is essential in neonatal surfactant production during respiratory adaptation.
abstract: Deficiency in pulmonary surfactant results in neonatal respiratory distress, and the known genetic mutations in key components of surfactant only account for a small number of cases. Therefore, determining the regulatory mechanisms of surfactant production and secretion, particularly during the transition from prenatal to neonatal stages, is essential for better understanding of the pathogenesis of human neonatal respiratory distress. We have observed significant increase of bone morphogenetic protein (BMP) signaling in neonatal mouse lungs immediately after birth. Using genetically manipulated mice, we then studied the relationship between BMP signaling and surfactant production in neonates. Blockade of endogenous BMP signaling by deleting Bmpr1a (Alk3) or Smad1 in embryonic day 18.5 in perinatal lung epithelial cells resulted in severe neonatal respiratory distress and death, accompanied by atelectasis in histopathology and significant reductions of surfactant protein B and C, as well as Abca3, whereas prenatal lung development was not significantly affected. We then identified a new BMP-Smad1 downstream target, Nfatc3, which is known as an important transcription activator for surfactant proteins and Abca3. Furthermore, activation of BMP signaling in cultured lung epithelial cells was able to promote endogenous Nfatc3 expression and also stimulate the activity of an Nfatc3 promoter that contains a Smad1-binding site. Therefore, our study suggests that the BMP-Alk3-Smad1-Nfatc3 regulatory loop plays an important role in enhancing surfactant production in neonates, possibly helping neonatal respiratory adaptation from prenatal amniotic fluid environment to neonatal air breathing.
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California;
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California;
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Respiratory Medicine, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, People's Republic of China;
authors.forename: Siying
authors.initials: S
authors.lastname: Ren
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California;
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Biologic and Material Sciences, University of Michigan, Ann Arbor, Michigan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California; wshi@chla.usc.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000222:Adaptation, Physiological; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D001665:Binding Sites; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D015870:Gene Expression; D008168:Lung / Q000254:growth & development / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011663:Pulmonary Surfactants / Q000378:metabolism*; D012119:Respiration; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D018528:ATP-Binding Cassette Transporters; C512026:Abca3 protein, mouse; D019485:Bone Morphogenetic Proteins; D011663:Pulmonary Surfactants; D051898:Smad1 Protein; C497401:Smad1 protein, mouse
keywords: Bmpr1a; Nfatc3; Smad1; lung development; neonatal respiratory distress