title: Id2 mediates oligodendrocyte precursor cell maturation arrest and is tumorigenic in a PDGF-rich microenvironment.
abstract: Maturation defects occurring in adult tissue progenitor cells have the potential to contribute to tumor development; however, there is little experimental evidence implicating this cellular mechanism in the pathogenesis of solid tumors. Inhibitor of DNA-binding 2 (Id2) is a transcription factor known to regulate the proliferation and differentiation of primitive stem and progenitor cells. Id2 is derepressed in adult tissue neural stem cells (NSC) lacking the tumor suppressor Tp53 and modulates their proliferation. Constitutive expression of Id2 in differentiating NSCs resulted in maturation-resistant oligodendroglial precursor cells (OPC), a cell population implicated in the initiation of glioma. Mechanistically, Id2 overexpression was associated with inhibition of the Notch effector Hey1, a bHLH transcription factor that we here characterize as a direct transcriptional repressor of the oligodendroglial lineage determinant Olig2. Orthotopic inoculation of NSCs with enhanced Id2 expression into brains of mice engineered to express platelet-derived growth factor in the central nervous system resulted in glioma. These data implicate a mechanism of altered NSC differentiation in glioma development and characterize a novel mouse model that reflects key characteristics of the recently described proneural subtype of glioblastoma multiforme. Such findings support the emerging concept that the cellular and molecular characteristics of tumor cells are linked to the transformation of distinct subsets of adult tissue progenitors.
authors.affiliation: Authors' Affiliations: Norris Cotton Cancer Center; Departments of Genetics; Pediatrics; and Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Havrda
authors.forename: Brenton R
authors.initials: BR
authors.lastname: Paolella
authors.forename: Cong
authors.initials: C
authors.lastname: Ran
authors.forename: Karola S
authors.initials: KS
authors.lastname: Jering
authors.forename: Christina M
authors.initials: CM
authors.lastname: Wray
authors.forename: Jaclyn M
authors.initials: JM
authors.lastname: Sullivan
authors.forename: Audrey
authors.initials: A
authors.lastname: Nailor
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Hitoshi
authors.forename: Mark A
authors.initials: MA
authors.lastname: Israel
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology* / Q000637:transplantation; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000502:physiology*; D011401:Promoter Regions, Genetic; D020574:Proto-Oncogene Proteins c-sis / Q000502:physiology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D051797:Inhibitor of Differentiation Protein 2; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D020574:Proto-Oncogene Proteins c-sis; D020796:Receptor, Platelet-Derived Growth Factor alpha; C485631:HEY1 protein, human; C497450:ID2 protein, human; C405708:OLIG2 protein, human