Publication date: Available online 29 September 2016
Author(s): Chiara Bardella, Osama Al-Dalahmah, Daniel Krell, Pijus Brazauskas, Khalid Al-Qahtani, Marketa Tomkova, Julie Adam, Sébastien Serres, Helen Lockstone, Luke Freeman-Mills, Inga Pfeffer, Nicola Sibson, Robert Goldin, Benjamin Schuster-Böeckler, Patrick J. Pollard, Tomoyoshi Soga, James S. McCullagh, Christopher J. Schofield, Paul Mulholland, Olaf Ansorge, Skirmantas Kriaucionis, Peter J. Ratcliffe, Francis G. Szele, Ian Tomlinson
Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H 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. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.
Bardella et al. report that expression of IDH1R132H in the subventricular zone of the adult mouse brain causes features of gliomagenesis, including increased numbers of neural stem cells, cellular infiltration into surrounding brain regions, and a gene expression profile overlapping that of human gliomas.
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