title: Homeobox, Wnt, and Fibroblast Growth Factor Signaling is Augmented During Alveogenesis in Mice Lacking Superoxide Dismutase 3, Extracellular.
abstract: Superoxide dismutase 3, extracellular (SOD3) polymorphisms have been implicated in reduced pulmonary function development and altered risk for chronic obstructive pulmonary disease. We previously reported that gene-targeted Sod3-/- mice have impaired lung function and human SOD3 variants are associated with reduced pulmonary function in children. Reduced lung SOD3 levels were reported in mice with lower lung function with the greatest difference occurring during alveogenesis phase [postnatal (P) days 14-28]. Interactions between homeobox (HOX), wingless-type MMTV integration site member (WNT), and fibroblast growth factor (FGF) signaling govern complex developmental processes in several organs. A subset of HOX family members, HOXA5 and HOXB5, is expressed in the developing lung. Therefore, in this study we assessed the transcript expression of these family members and their downstream targets in Sod3-/- mice during alveogenesis (P14). In the lung of Sod3-/- mice, Hoxa5 and Hoxb5 increased. These transcription factors regulate WNT gene expression and were accompanied by increases in their downstream targets Wnt2 and Wnt5A, canonical and noncanonical WNT members, respectively. The WNT signaling target, lymphoid enhancer binding factor 1 (Lef1), also increased along with its downstream targets Fgf2, Fgf7, and Fgf10 in the lungs of Sod3-/- mice. Due to limited knowledge on the role of FGF2 in lung development, we further examined FGF2 protein and found increased levels in the bronchial and alveolar type II epithelial cells of Sod3-/- mice compared to age-matched controls. Thus, our findings suggest that deficient management of extracellular superoxide can lead to altered lung developmental signaling during alveogenesis in mice.
authors.affiliation: SRM Research Institute, SRM University, Chennai, 603203, India.
authors.forename: Tania A
authors.initials: TA
authors.lastname: Thimraj
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
authors.forename: Rahel L
authors.initials: RL
authors.lastname: Birru
authors.affiliation: SRM Research Institute, SRM University, Chennai, 603203, India.
authors.forename: Ankita
authors.initials: A
authors.lastname: Mitra
authors.affiliation: Institute of Epidemiology I, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, 85764, Munich, Germany.|Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Munich, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Schulz
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Leikauf
authors.affiliation: SRM Research Institute, SRM University, Chennai, 603203, India. koustav.ganguly@ki.se.|Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15219, USA. koustav.ganguly@ki.se.|Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Box 287, 171 77, Stockholm, Sweden. koustav.ganguly@ki.se.|Work Environment Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 287, 171 77, Stockholm, Sweden. koustav.ganguly@ki.se.
authors.forename: Koustav
authors.initials: K
authors.lastname: Ganguly
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000235:genetics; D000072261:Dishevelled Proteins / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D051526:Fibroblast Growth Factor 10 / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000378:metabolism; D051523:Fibroblast Growth Factor 7 / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D051157:Frizzled Receptors / Q000235:genetics; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics; D011650:Pulmonary Alveoli / Q000254:growth & development*; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway / Q000235:genetics*; D000071818:Wnt-5a Protein / Q000235:genetics; D051154:Wnt2 Protein / Q000235:genetics
chemical_list: D060466:Axin Protein; C111729:Axin2 protein, mouse; D000072261:Dishevelled Proteins; C000606585:Dvl3 protein, mouse; C496464:Fgf10 protein, mouse; C496454:Fgf7 protein, mouse; D051526:Fibroblast Growth Factor 10; D051157:Frizzled Receptors; C489739:Fzd1 protein, mouse; C489743:Fzd2 protein, mouse; D018398:Homeodomain Proteins; C059637:Hoxa5 protein, mouse; C053925:Hoxb5 protein, mouse; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D010750:Phosphoproteins; D014157:Transcription Factors; D000071818:Wnt-5a Protein; D051154:Wnt2 Protein; C438615:Wnt5a protein, mouse; D016222:Fibroblast Growth Factor 2; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase
keywords: FGF; Lung development; Oxidative stress; Superoxide; WNT