Expression of Idh1(R132H) in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
- University of Oxford
- Department of Oncology, Cancer Research UK and MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7LE, UK; School of Life Sciences, The Medical School, University of Nottingham, Nottingham NG7 2UH, UK.
- Imperial College London
- Hypoxia Biology Laboratory, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK; Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, 405 30 Gothenburg, Sweden.
- Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan.
- University College London Hospitals NHS Foundation Trust
- Nuffield Department of Clinical Neurosciences, Department of Neuropathology, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1(R132H) in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells overexpressed Wnt, cell-cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1(R132H) mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.
|Number of pages||17|
|Early online date||29 Sep 2016|
|Publication status||Published - 10 Oct 2016|
- Animals, Brain Neoplasms, DNA Methylation, Glioma, Isocitrate Dehydrogenase, Lateral Ventricles, Mice, Mice, Transgenic, Mutation, Neoplastic Stem Cells, Stem Cell Niche, Transcriptome, Journal Article