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| 2. |
- Hede, Sanna-Maria, et al.
(författare)
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GFAP promoter driven transgenic expression of PDGFB in the mouse brain leads to glioblastoma in a Trp53 null background
- 2009
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Ingår i: Glia. - : Wiley. - 0894-1491 .- 1098-1136. ; 57:11, s. 1143-1153
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastomas are the most common and malignant astrocytic brain tumors in human adults. The tumor suppressor gene TP53 is commonly mutated and/or lost in astrocytic brain tumors and the TP53 alterations are often found in combination with excessive growth factor signaling via PDGF/PDGFRalpha. Here, we have generated transgenic mice over-expressing human PDGFB in brain, under control of the human GFAP promoter. These mice showed no phenotype, but on a Trp53 null background a majority of them developed brain tumors. This occurred at 2-6 months of age and tumors displayed human glioblastoma-like features with integrated development of Pdgfralpha+ tumor cells and Pdgfrbeta+/Nestin+ vasculature. The transgene was expressed in subependymal astrocytic cells, in glia limitans, and in astrocytes throughout the brain substance, and subsequently, microscopic tumor lesions were initiated equally in all these areas. With tumor size, there was an increase in Nestin positivity and variability in lineage markers. These results indicate an unexpected plasticity of all astrocytic cells in the adult brain, not only of SVZ cells. The results also indicate a contribution of widely distributed Pdgfralpha+ precursor cells in the tumorigenic process.
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| 3. |
- Toepoel, Mascha, et al.
(författare)
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Haplotype-specific expression of the human PDGFRA gene correlates with the risk of glioblastomas
- 2008
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 123:2, s. 322-329
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Tidskriftsartikel (refereegranskat)abstract
- Aberrant expression of the platelet-derived growth factor a-receptor (PDGFRA) gene has been associated with various diseases, including neural tube defects and gliomas. We have previously identified 5 distinct haplotypes for the PDGFRA promoter region, designated H1, H2 alpha, H2 beta, H2 gamma and H2 delta. Of these haplotypes H1 and H2 alpha: are the most common, whereby H1 drives low and H2 alpha high transcriptional activity in transient transfection assays. Here we have investigated the role of these PDGFRA promoter haplotypes in gliomagenesis at both the genetic and cellular level. In a case-control study on 71 glioblastoma patients, we observed a clear underrepresentation of H1 alleles, with pH1 = 0.141 in patients and pH1 = 0.211 in a combined Western European control group (n = 998, p < ; 0.05). Furthermore, in 3 out of 4 available H1/H2 alpha heterozygous human glioblastoma cell lines, H1-derived mRNA levels were more than 10-fold lower than from H2 alpha, resulting at least in part from haplotype-specific epigenetic differences such as DNA methylation and histone acetylation. Together, these results indicate that PDGFRA promoter haplotypes may predispose to gliomas. We propose a model in which PDGFRA is upregulated in a haplotype-specific manner during neural stem cell differentiation, which affects the pool size of cells that can later undergo gliomagenesis.
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| 4. |
- Zhang, Xiao-Qun, et al.
(författare)
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Gli1 is not required for Pdgfralpha expression during mouse embryonic development
- 2005
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Ingår i: Differentiation. - : Elsevier BV. - 0301-4681 .- 1432-0436. ; 73:2-3, s. 109-19
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Tidskriftsartikel (refereegranskat)abstract
- Pdgfra is expressed in the mesenchyme of multiple organs during embryonic development and Pdgfrα is involved in cell proliferation, differentiation, migration, and apoptosis in many tissues. A fine-tuned regulation of gene transcription is required to achieve these effects. To investigate if the Shh signaling pathway is involved in the tightly regulated Pdgfra expression during embryogenesis, we systematically compared Gli1 and Pdgfrα mRNA expression patterns in vivo from mouse embryonic day 9.5 to 14.5. We found that an initial partly overlapping expression of Gli1 and Pdgfrα in the mesenchyme of foregut and somites was changed to different expression patterns when the mesenchyme differentiated into specialized structures such as intestinal villi and chondrocytes. Gli1 and Pdgfra were also expressed differently in the developing lung, heart, central nervous system, skin, tooth, and eye. Importantly, neither Pdgfrα mRNA patterns nor levels were altered in Ihh mutant embryos although Gli1 and Ptc mRNA levels were dramatically reduced. Our results demonstrate that Gli1 is not required to induce Pdgfra expression during embryonic bone development, and are consistent with previous findings that Pdgfrα and Hh pathways serve different functions in, e.g., bone, gut, and lung development. However, we cannot exclude the possibility that Glis can have more complex regulatory effects on Pdgfra gene activity, nor can we exclude such effects in pathological conditions.
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| 5. |
- Zhang, Xiao-Qun, et al.
(författare)
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Specific expression in mouse mesoderm- and neural crest-derived tissues of a human PDGFRA promoter/lacZ transgene
- 1998
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Ingår i: Mechanisms of Development. - 0925-4773 .- 1872-6356. ; 70:1-2, s. 167-180
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Tidskriftsartikel (refereegranskat)abstract
- The platelet-derived growth factor alpha-receptor (PDGFR-alpha) displays a lineage-specific expression pattern in the mouse embryo and is required for normal development of mesoderm and cephalic neural crest derivatives. The purpose of the present study was to demonstrate the in vivo promoter function of genomic DNA fragments representing the 5'-flanking part of the human PDGFRA gene. 2.2, 0.9 and 0.4 kb PDGFRA promoter fragments, ligated to a lacZ reporter gene, were microinjected into fertilized mouse eggs and transgenic mouse lines were established. The expression patterns were basically similar in the 2.2 and 0.9 kb lines and overlapped grossly the endogenous Pdgfra gene expression pattern. The transgenic line with the highest expression level was chosen for detailed analysis. Expression was, as expected, mainly confined to tissues of mesodermal and neural crest origin. No expression was found in epithelial tissues of endo- or ectodermal origin. The promoter fragments were also active in neuroepithelium and in certain neuronal cell types that did not faithfully express PDGFR-alpha mRNA, while they failed to specify reporter expression in PDGFR-alpha expressing O-2A progenitor cells and other glial elements of the central nervous system. Thus, the isolated human PDGFRA promoter contains most but not all of the regulatory elements that are necessary to establish tissue specific gene expression during development.
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