Ets Factors Regulate Neural Stem Cell Depletion and Gliogenesis in Ras Pathway Glioma

• Rapid brain tumor modeling with postnatal electroporation and transposon methodology
• Modeling methodology allows for extensive interrogation of tumor growth mechanisms
• Ras pathway mutations deplete neural stem cells and upregulate Ets factors
• Ets signaling block rescues Ras-mediated stem cell loss and prevents tumor formation

SummaryAs the list of putative driver mutations in glioma grows, we are just beginning to elucidate the effects of dysregulated developmental signaling pathways on the transformation of neural cells. We have employed a postnatal, mosaic, autochthonous glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional genetically engineered mouse models of cancer. We provide evidence that disruption of the Nf1-Ras pathway in the ventricular zone at multiple signaling nodes uniformly results in rapid neural stem cell depletion, progenitor hyperproliferation, and gliogenic lineage restriction. Abolishing Ets subfamily activity, which is upregulated downstream of Ras, rescues these phenotypes and blocks glioma initiation. Thus, the Nf1-Ras-Ets axis might be one of the select molecular pathways that are perturbed for initiation and maintenance in glioma.

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