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Expression analysis of platelet-derived growth factor receptor alpha and its ligands in the developing mouse lung
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Integrated Cardio Metab Ctr, Huddinge, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.ORCID iD: 0000-0003-0700-4381
2017 (English)In: Physiological Reports, E-ISSN 2051-817X, Vol. 5, no 6, article id e13092Article in journal (Refereed) Published
Abstract [en]

Activation of the platelet-derived growth factor receptor-a (PDGFRa) signaling pathway is critically important during lung alveogenesis, the process in lung development during which alveoli are formed from the terminal alveolar sacs. Several studies have aimed to characterize the expression patterns of PDGFRa and its two ligands (PDGF-A and -C) in the lung, but published analyses have been limited to embryonic and/or perinatal time points, and no attempts have been made to characterize both receptor and ligand expression simultaneously. In this study, we present a detailed map of the expression patterns of PDGFRa, PDGF-A and PDGF-C during the entire period of lung development, that is, from early embryogenesis until adulthood. Three different reporter mice were analyzed (Pdgfa ex4-COIN-INV-lacZ, Pdgfc tm1Nagy, and Pdgfra tm11(EGFP) Sor), in which either lacZ or H2B-GFP were expressed under the respective promoter in gene-targeted alleles. A spatiotemporal dynamic expression was identified for both ligands and receptor. PDGF-A and PDGF-C were located to distinct populations of epithelial and smooth muscle cells, whereas PDGFRa expression was located to different mesenchymal cell populations. The detailed characterization of gene expression provides a comprehensive map of PDGFRa signaling in lung cells, opening up for a better understanding of the role of PDGF signaling during lung development.

Place, publisher, year, edition, pages
WILEY , 2017. Vol. 5, no 6, article id e13092
Keywords [en]
Lung, platelet-derived growth factor, platelet-derived growth factor receptors, signal transduction
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-320399DOI: 10.14814/phy2.13092ISI: 000397435300007OAI: oai:DiVA.org:uu-320399DiVA, id: diva2:1089516
Funder
Magnus Bergvall FoundationSwedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg FoundationEU, European Research CouncilAvailable from: 2017-04-20 Created: 2017-04-20 Last updated: 2018-05-18Bibliographically approved
In thesis
1. The role of PDGF-A in lung development, injury and repair
Open this publication in new window or tab >>The role of PDGF-A in lung development, injury and repair
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The developmental processes that take place during embryogenesis depend on a great number of proteins that are important for cell-to-cell communication. Platelet-derived growth factors are known to be important for epithelial-mesenchymal interactions during development and organogenesis. However, many details are still lacking regarding organ-specific PDGF expression patterns and detailed cellular functions. This thesis aims to better describe the contribution of PDGF-A signaling to lung developmental and injury processes.

To study the cell-specific expression patterns of PDGF-A we generated a reporter mouse that show LacZ expression in all PDGF-A positive cells. This mouse model was used to characterize PDGF-A expression in embryonic and adult mouse tissues (paper I).

With the use of three different reporter mice, we described the cell type specific expression patterns of PDGF-A, PDGF-C and PDGFRα in mouse lungs, from embryonic day 10.5 (E10.5) when development is initiated, until adulthood (Postnatal day 60) when the lung is fully mature (paper II).

A lung-specific Pdgfa knockout mouse was generated and the impact of the deletion was studied during lung development and adulthood. Mice lacking Pdgfa expression in the lung survived until adulthood but exhibited abnormal alveolar development. This phenotype was caused by the inability of myofibroblasts to assemble alpha smooth muscle actin ring around the forming alveoli (paper III).

To investigate if PDGF-A is involved in the injury response mechanisms of the adult lung, we generated inducible lung-specific Pdgfa knockout mice. In homeostasis, adult Pdgfa deletion did not result in any apparent phenotype, whereas after hyperoxia-induced lung injury, preliminary data show that mutant mice exhibit substantially more alveolar damage and immune cell infiltration (paper IV).

In conclusion, this thesis reports novel insights into the expression and role of PDGF-A and PDGFRα for the lung, both in development and adulthood.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 53
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1448
Keywords
Lung, organogenesis, PDGF, signalling pathway, development
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-347032 (URN)978-91-513-0291-1 (ISBN)
Public defence
2018-05-18, Rudbecksalen, Dag Hammarskjöls väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-04-27 Created: 2018-03-23 Last updated: 2018-05-23

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