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Characterization of Platelet-Derived Growth Factor-A Expression in Mouse Tissues Using a lacZ Knock-In Approach
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.ORCID iD: 0000-0003-0700-4381
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e105477-Article in journal (Refereed) Published
Abstract [en]

Expression of the platelet-derived growth factor A-chain gene (Pdgfa) occurs widely in the developing mouse, where it is mainly localized to various epithelial and neuronal structures. Until now, in situ mRNA hybridization (ISH) has been the only reliable method to identify Pdgfa expression in tissue sections or whole mount preparations. Validated protocols for in situ detection of PDGF-A protein by immunohistochemistry is lacking. In particular, this has hampered understanding of Pdgfa expression pattern in adult tissues, where ISH is technically challenging. Here, we report a gene targeted mouse Pdgfa allele, Pdgfa(ex4COIN), which is a combined conditional knockout and reporter allele. Cre-mediated inversion of the COIN cassette inactivates Pdgfa coding while simultaneously activating a beta-galactosidase (lacZ) reporter under endogenous Pdgfa transcription control. The generated Pdgfa(ex4COIN-INV-lacZ) allele can next be used to identify cells carrying a Pdgfa null allele, as well as to map endogenous Pdgfa expression. We evaluated the Pdgfa(ex4COIN-INV-lacZ) allele as a reporter for endogenous Pdgfa expression patterns in mouse embryos and adults. We conclude that the expression pattern of Pdgfa(ex4COIN-INV-lacZ) recapitulates known expression patterns of Pdgfa. We also report on novel embryonic and adult Pdgfa expression patterns in the mouse and discuss their implications for Pdgfa physiology.

Place, publisher, year, edition, pages
2014. Vol. 9, no 8, p. e105477-
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-233014DOI: 10.1371/journal.pone.0105477ISI: 000341303700027OAI: oai:DiVA.org:uu-233014DiVA, id: diva2:753701
Funder
Swedish Cancer Society, 2012/433EU, European Research Council, 294556
Available from: 2014-10-08 Created: 2014-09-29 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
Keyword
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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