title: Brain abnormalities and glioma-like lesions in mice overexpressing the long isoform of PDGF-A in astrocytic cells.
abstract: BACKGROUND
  Deregulation of platelet-derived growth factor (PDGF) signaling is a hallmark of malignant glioma. Two alternatively spliced PDGF-A mRNAs have been described, corresponding to a long (L) and a short (S) isoform of PDGF-A. In contrast to PDGF-A(S), the PDGF-A(L) isoform has a lysine and arginine rich carboxy-terminal extension that acts as an extracellular matrix retention motif. However, the exact role of PDGF-A(L) and how it functionally differs from the shorter isoform is not well understood.
  
  
  RESULTS
  We overexpressed PDGF-A(L) as a transgene under control of the glial fibrillary acidic protein (GFAP) promoter in the mouse brain. This directs expression of the transgene to astrocytic cells and GFAP expressing neural stem cells throughout the developing and adult central nervous system. Transgenic mice exhibited a phenotype with enlarged skull at approximately 6-16 weeks of age and they died between 1.5 months and 2 years of age. We detected an increased number of undifferentiated cells in all areas of transgene expression, such as in the subependymal zone around the lateral ventricle and in the cerebellar medulla. The cells stained positive for Pdgfr-α, Olig2 and NG2 but this population did only partially overlap with cells positive for Gfap and the transgene reporter. Interestingly, a few mice presented with overt neoplastic glioma-like lesions composed of both Olig2 and Gfap positive cell populations and with microvascular proliferation, in a wild-type p53 background.
  
  
  CONCLUSIONS
  Our findings show that PDGF-A(L) can induce accumulation of immature cells in the mouse brain. The strong expression of NG2, Pdgfr-α and Olig2 in PDGF-A(L) brains suggests that a fraction of these cells are oligodendrocyte progenitors. In addition, accumulation of fluid in the subarachnoid space and skull enlargement indicate that an increased intracranial pressure contributed to the observed lethality.
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Inga
authors.initials: I
authors.lastname: Nazarenko
authors.forename: Anna
authors.initials: A
authors.lastname: Hedrén
authors.forename: Hanna
authors.initials: H
authors.lastname: Sjödin
authors.forename: Abiel
authors.initials: A
authors.lastname: Orrego
authors.forename: Johanna
authors.initials: J
authors.lastname: Andrae
authors.forename: Gijs B
authors.initials: GB
authors.lastname: Afink
authors.forename: Monica
authors.initials: M
authors.lastname: Nistér
authors.forename: Mikael S
authors.initials: MS
authors.lastname: Lindström
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein; D005910:Glioma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005904:Glial Fibrillary Acidic Protein; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D010982:Platelet-Derived Growth Factor; D020033:Protein Isoforms; D055748:SOXB1 Transcription Factors; C512773:Olig2 protein, mouse; C527783:Sox2 protein, mouse; C528900:glial fibrillary astrocytic protein, mouse; C075278:platelet-derived growth factor A