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Homeobox, Wnt, and Fibroblast Growth Factor Signaling is Augmented During Alveogenesis in Mice Lacking Superoxide Dismutase 3, Extracellular

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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.

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Acknowledgements

The authors acknowledge the technical assistance received from Joseph D. Latoche, Department of Environmental and Occupational Health, University of Pittsburgh, PA, USA. The authors also thank Dr. Cheryl L. Fattman for providing the gene-targeted Sod3−/−mice.

Author Contributions

HS, GDL, and KG conceived and designed the study; TAT, RLB, and KG performed the experiments; TAT, RLB, AM, HS, GDL, and KG analyzed and interpreted the data; TAT, HS, GDL, and KG wrote the manuscript.

Funding

This study was supported by DST SERB: SB/SO/AS-026/2013; Department of Biotechnology, Government of India: BT/PR12987/INF/22/205/2015, VINNOVA (2016-01951) (KG); NIH: NIEHS ES015675 (GDL); CSIR-SRF: [9/1045(0007) 2K14-EMR-1]; and Fulbright Nehru Doctoral Research Fellowship (IIE grantee ID 15151382) (TAT).

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    Authors and Affiliations

    1. SRM Research Institute, SRM University, Chennai, 603203, India

      Tania A. Thimraj, Ankita Mitra & Koustav Ganguly

    2. Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15219, USA

      Rahel L. Birru, George D. Leikauf & Koustav Ganguly

    3. Institute of Epidemiology I, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, 85764, Munich, Germany

      Holger Schulz

    4. Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Munich, Germany

      Holger Schulz

    5. Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Box 287, 171 77, Stockholm, Sweden

      Koustav Ganguly

    6. Work Environment Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 287, 171 77, Stockholm, Sweden

      Koustav Ganguly

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    1. Tania A. Thimraj
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    Correspondence to Koustav Ganguly.

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    George D. Leikauf and Koustav Ganguly have contributed equally.

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    Thimraj, T.A., Birru, R.L., Mitra, A. et al. Homeobox, Wnt, and Fibroblast Growth Factor Signaling is Augmented During Alveogenesis in Mice Lacking Superoxide Dismutase 3, Extracellular. Lung 195, 263–270 (2017). https://doi.org/10.1007/s00408-017-9980-x

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