Expression of Idh1R132H in the murine subventricular zone stem cell niche recapitulates features of early gliomagenesis
Authors list
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 Ratcliffe Francis G Szele Ian TomlinsonAbstract
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 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 mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.
Journal details
Journal Cancer Cell
Volume 30
Issue number 4
Pages 578-594
Available online
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Publisher website (DOI) 10.1016/j.ccell.2016.08.017
Europe PubMed Central 27693047
Pubmed 27693047
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