The cell of origin dictates the temporal course of neurofibromatosis-1 (Nf1) low-grade glioma formation

Anne C. Solga, Joseph A. Toonen, Yuan Pan, Patrick J. Cimino, Yu Ma, Guillaume A. Castillon, Scott M. Gianino, Mark H. Ellisman, Da Yong Lee, David H. Gutmann

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Low-grade gliomas are one of the most common brain tumors in children, where they frequently form within the optic pathway (optic pathway gliomas; OPGs). Since many OPGs occur in the context of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome, we have previously employed Nf1 genetically-engineered mouse (GEM) strains to study the pathogenesis of these low-grade glial neoplasms. In the light of the finding that human and mouse low-grade gliomas are composed of Olig2+ cells and that Olig2+ oligodendrocyte precursor cells (OPCs) give rise to murine high-grade gliomas, we sought to determine whether Olig2+ OPCs could be tumorinitiating cells for Nf1 optic glioma. Similar to the GFAP-Cre transgenic strain previously employed to generate Nf1 optic gliomas, Olig2+ cells also give rise to astrocytes in the murine optic nerve in vivo. However, in contrast to the GFAP-Cre strain where somatic Nf1 inactivation in embryonic neural progenitor/stem cells (Nf1flox/mut; GFAP-Cre mice) results in optic gliomas by 3 months of age in vivo, mice with Nf1 gene inactivation in Olig2+ OPCs (Nf1flox/mut; Olig2-Cre mice) do not form optic gliomas until 6 months of age. These distinct patterns of glioma latency do not reflect differences in the timing or brain location of somatic Nf1 loss. Instead, they most likely reflect the cell of origin, as somatic Nf1 loss in CD133+ neural progenitor/stem cells during late embryogenesis results in optic gliomas at 3 months of age. Collectively, these data demonstrate that the cell of origin dictates the time to tumorigenesis in murine optic glioma.

Original languageEnglish
Pages (from-to)47206-47215
Number of pages10
JournalOncotarget
Volume8
Issue number29
DOIs
StatePublished - 2017

Keywords

  • Astrocytoma
  • NF1
  • OPC
  • Pediatric brain tumor
  • Tumorigenesis

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