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Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. (Mats Hellström)
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.; Department of Neurology, Friedrich-Baur-Institut, Ludwig-Maximilians-Universität München, Munich, Germany.
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 15453Article in journal (Refereed) Published
Abstract [en]

Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.

Place, publisher, year, edition, pages
2017. Vol. 7, no 15453
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-281704DOI: 10.1038/s41598-017-14894-9ISI: 000415023200014PubMedID: 29133847OAI: oai:DiVA.org:uu-281704DiVA, id: diva2:920466
Funder
Swedish Cancer SocietyÅke Wiberg Foundation
Note

List of authors in thesis manuscript: Egaña I, Nitzsche A, Kaito H, Becker L, Garrett L, Niaudet C, Liu W, Vanlandewijck M, Larsson J, Hrabe de Angelis M, Fuchs H, Gailus-Durner V, Vernaleken A, Klopstock T, Hölter S M, Wurst W, Rask-Andersen H, German Mouse Clinic Consortium, Yildirim A Ö, Hellström M

Available from: 2016-04-18 Created: 2016-03-29 Last updated: 2018-02-22Bibliographically approved
In thesis
1. The Role of Paladin in Endothelial Cell Signaling and Angiogenesis
Open this publication in new window or tab >>The Role of Paladin in Endothelial Cell Signaling and Angiogenesis
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Angiogenesis, the formation of new blood vessels from a pre-existing vasculature, is crucial during development and for many diseases including cancer. Despite tremendous progress in the understanding of the angiogenic process, many aspects are still not fully elucidated. Several attempts have been made to identify novel genes involved in endothelial cell biology and angiogenesis. Here we focused on Pald1, a recently identified, vascular-enriched gene encoding paladin. Our in vitro studies indicate that paladin is a lipid phosphatase catalyzing dephosphorylation of phosphatidylinositol phosphates, a process essential for endocytosis and intracellular vesicle trafficking.

We confirmed paladin’s vascular expression pattern and revealed a shift from a broad endothelial cell expression during development to an arterial mural cell-restricted expression in several vascular beds in adult mice. Paladin expression in the lung, however, was not restricted to the vasculature, but was also observed in pneumocytes and myofibroblasts. Lungs of female, but not male, Pald1 null mice displayed an obstructive lung phenotype with increased alveolar air sacs that were already apparent early in the alveolarization process. Only endothelial cells, but not other main lung cell types, were affected by loss of paladin. Endothelial cell number was reduced in 4-week old mice, possibly due to increased endothelial turnover in Pald1 deficient lungs.

Vascular defects were also found in the retina. Loss of paladin led to reduced retinal vascular outgrowth accompanied by a hyperdense and hypersprouting vascular front. Downstream signaling of the major angiogenic driver, vascular endothelial growth factor receptor 2 (VEGFR2) was sustained in Pald1 null mice, and VEGFR2 degradation was impaired. Furthermore, paladin inhibited endothelial cell junction stability and loss of paladin led to reduced vascular permeability.

Whether the differences in VEGFR2 signaling and adherens junction stability are connected remains to be fully explored. The newly identified lipid phosphatase activity of paladin and its specific effects on VEGFR2 signaling and adherens junction stability indicate that paladin may be controlling the endocytic pathway.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. p. 47
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1225
Keyword
Pald1, endothelium, lung, vascular permeability, phosphatase, angiogenesis
National Category
Cell and Molecular Biology
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-281708 (URN)978-91-554-9578-7 (ISBN)
Public defence
2016-06-09, Rudbecksalen (C11), Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Supervisors
Available from: 2016-05-19 Created: 2016-03-29 Last updated: 2018-01-10

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Nitzsche, AnjaNiaudet, ColinHe, LiqunHellström, Mats

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