title: Antagonistic modulation of gliomagenesis by Pax6 and Olig2 in PDGF-induced oligodendroglioma.
abstract: Gliomas are aggressive tumors of the central nervous system originating from proliferating neural cells. Regulators of neural stem or progenitor cells biology may thus influence aspects of brain tumorigenesis, such as the maintenance of tumor-propagating potential. We investigated the role of Pax6, a neurogenic transcription factor already suggested as a positive prognostic marker for human gliomas, in a well-characterized in vivo model of PDGF-B-driven oligodendroglioma. In this system, the expression of Pax6 severely impairs tumor propagation by inducing a reduction of cell proliferation and the acquisition of differentiation traits in tumor-initiating cells. The overexpression of Pax6 correlates with a downregulation of Olig2, a bHLH transcription factor that normally antagonizes Pax6 in adult neurogenic niches and that plays a key role in the maintenance of neural stem and progenitor cells. Furthermore, we found that Olig2 is strictly required to maintain the malignancy of oligodendroglioma cells, since its silencing by interfering RNA abrogates tumor propagation. We finally show evidence that this function depends, at least in part, on the silencing of ID4, a dominant negative bHLH protein, whose upregulation follows Olig2 loss. In our model, the upregulation of ID4 mimics the loss of Olig2 in impairing the tumor-propagating potential of glioma cells. Our data, therefore, establish the relevance of physiological regulators of neural stem cell biology in regulating glial tumor malignancy and provide support for their functional interactions in this context.
authors.affiliation: Department of Experimental Medicine, DIMES, University of Genoa, Genoa 16132, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Appolloni
authors.forename: Filippo
authors.initials: F
authors.lastname: Calzolari
authors.forename: Manuela
authors.initials: M
authors.lastname: Barilari
authors.forename: Marta
authors.initials: M
authors.lastname: Terrile
authors.forename: Antonio
authors.initials: A
authors.lastname: Daga
authors.forename: Paolo
authors.initials: P
authors.lastname: Malatesta
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics*; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics*; D000076104:Oligodendrocyte Transcription Factor 2; D009837:Oligodendroglioma / Q000235:genetics* / Q000378:metabolism; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D051796:Inhibitor of Differentiation Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D010982:Platelet-Derived Growth Factor; D012097:Repressor Proteins; C086479:Idb4 protein, mouse; C512773:Olig2 protein, mouse; C000605730:PAX6 protein, human; C000605732:Pax6 protein, mouse