title: Regulation of alveolar septation by microRNA-489.
abstract: MicroRNAs (miRs) are small conserved RNA that regulate gene expression. Bioinformatic analysis of miRNA profiles during mouse lung development indicated a role for multiple miRNA, including miRNA-489. miR-489 increased on completion of alveolar septation [postnatal day 42 (P42)], associated with decreases in its conserved target genes insulin-like growth factor-1 (Igf1) and tenascin C (Tnc). We hypothesized that dysregulation of miR-489 and its target genes Igf1 and Tnc contribute to hyperoxia-induced abnormal lung development. C57BL/6 mice were exposed to normoxia (21%) or hyperoxia (85% O2) from P4 to P14, in combination with intranasal locked nucleic acid against miR-489 to inhibit miR-489, cytomegalovirus promoter (pCMV)-miR-489 to overexpress miR-489, or empty vector. Hyperoxia reduced miR-489 and increased Igf1 and Tnc. Locked nucleic acid against miR-489 improved lung development during hyperoxia and did not alter it during normoxia, whereas miR-489 overexpression inhibited lung development during normoxia. The 3' untranslated region in vitro reporter studies confirmed Igf1 and Tnc as targets of miR-489. While miR-489 was of epithelial origin and present in exosomes, its targets Igf1 and Tnc were produced by fibroblasts. Infants with bronchopulmonary dysplasia (BPD) had reduced lung miR-489 and increased Igf1 and Tnc compared with normal preterm or term infants. These results suggest increased miR-489 is an inhibitor of alveolar septation. During hyperoxia or BPD, reduced miR-489 and increased Igf1 and Tnc may be inadequate attempts at compensation. Further inhibition of miR-489 may permit alveolar septation to proceed. The use of specific miRNA antagonists or agonists may be a therapeutic strategy for inhibited alveolarization, such as in BPD.
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Nelida
authors.initials: N
authors.lastname: Olave
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Charitharth V
authors.initials: CV
authors.lastname: Lal
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Brian
authors.initials: B
authors.lastname: Halloran
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Kusum
authors.initials: K
authors.lastname: Pandit
authors.affiliation: Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri;
authors.forename: Alain C
authors.initials: AC
authors.lastname: Cuna
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Ona M
authors.initials: OM
authors.lastname: Faye-Petersen
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: David R
authors.initials: DR
authors.lastname: Kelly
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Teodora
authors.initials: T
authors.lastname: Nicola
authors.affiliation: Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors.forename: Panayiotis V
authors.initials: PV
authors.lastname: Benos
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama; Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; nambalavanan@peds.uab.edu.
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D011650:Pulmonary Alveoli / Q000378:metabolism*
chemical_list: C552418:MIRN489 microRNA, human; C570982:MIRN489 microRNA, mouse; D035683:MicroRNAs
keywords: infant; lung development; microRNAs; newborn