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An activating mutation in the PDGF receptor-beta causes abnormal morphology in the mouse placenta
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
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2007 (English)In: International Journal of Developmental Biology, ISSN 0214-6282, E-ISSN 1696-3547, Vol. 51, no 5, 361-370 p.Article in journal (Refereed) Published
Abstract [en]

An oncogenic D842V mutation in the platelet-derived growth factor (PDGF) alpha-receptor (Pdgfra) has recently been described in patients with gastrointestinal stromal tumors. In order to test if the same mutation would confer oncogenic properties to the homologous PDGF beta-receptor (Pdgfrb), the corresponding aspartic acid residue at position 849 of Pdgfrb was changed into valine (D849V) using a knock-in strategy. This mutation turned out to be dominantly lethal and caused death even in chimeras (from 345 transferred chimeric blastocysts, no living coat chimeras were detected). Experiments employing mouse embryonic fibroblasts (MEFs) indicated hyperactivity of the mutant receptor. The mutant receptor was phosphorylated in a ligand-independent manner and, in contrast to wild-type MEFs, mutant cells proliferated even in the absence of ligand. Knockout experiments have previously indicated a role for Pdgfrb in placental development. We therefore analyzed wild-type and Pdgfrb D849V chimeric placentas from different gestational stages. No differences were detected at embryonic days 11.5 and 13.5 (n=4). At embryonic day 17.5, however, chimeric placentas (n=3/4) displayed abnormalities both in the labyrinth and in the chorionic plate. The changes included hyper-proliferation of alpha-smooth muscle actin and platelet/endothelial cell adhesion molecule-1 positive cells in the labyrinth and cells in the chorionic plate. In addition, the fetal blood vessel compartment of the labyrinth was completely disorganized.

Place, publisher, year, edition, pages
2007. Vol. 51, no 5, 361-370 p.
Keyword [en]
Gene targeting, pericyte, labyrinthine layer, growth factor signaling
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Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-11693DOI: 10.1387/ijdb.072301clISI: 000249067500002PubMedID: 17616925OAI: oai:DiVA.org:uu-11693DiVA: diva2:39462
Available from: 2008-05-15 Created: 2008-05-15 Last updated: 2017-12-11Bibliographically approved

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Yu, YangZieba, AgataÅhgren, AiveHellberg, CarinaHeldin, Carl-HenrikZhang, X-QForsberg-Nilsson, KarinFundele, ReinaldHeuchel, Rainer

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Yu, YangZieba, AgataÅhgren, AiveHellberg, CarinaHeldin, Carl-HenrikZhang, X-QForsberg-Nilsson, KarinFundele, ReinaldHeuchel, Rainer
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Ludwig Institute for Cancer ResearchAnimal Development and GeneticsDepartment of Medical Biochemistry and MicrobiologyDepartment of Physiology and Developmental Biology
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