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 tumor-initiating 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.
Highlights
Low-grade glial neoplasms account for the majority of brain tumors in children between the ages of five and fifteen
Since many optic pathway gliomas (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
Summary
Low-grade glial neoplasms (pilocytic astrocytoma; PA) account for the majority of brain tumors in children between the ages of five and fifteen. While the majority of PAs developing within the cerebellum harbor BRAF gene rearrangements [1], one of the most common genetic etiologies for optic pathway gliomas (OPGs) is the neurofibromatosis type 1 (NF1) inherited cancer syndrome Unlike their sporadic counterparts, these NF1-OPGs result from bi-allelic inactivation of the NF1 tumor suppressor gene [2,3,4]. Since human NF1-OPGs are rarely biopsied and patient-derived xenografts are unavailable, the majority of our insights into pathogenesis of these tumors have derived from the use of genetically-engineered mouse (GEM) strains [10, 11] These GEM models have been informative for preclinical therapeutic drug discovery and evaluation, resulting in the identification of mechanistic target of rapamycin and MEK as potential targets for optic glioma treatment [12,13,14], under evaluation in human clinical trials. We employ two distinct Cre transgenic mouse strains, in which somatic Nf1 gene inactivation occurs in Olig2+ glial progenitor cells or CD133+ neural progenitor/stem cells, to demonstrate that the cell of origin is one major determinant in dictating the temporal course of optic gliomagenesis in mice
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
