Abstract
During cortical gliogenesis, tri-potential intermediate progenitor cells (Tri-IPCs) differentiate into oligodendrocyte precursor cells (OPCs) or olfactory bulb interneuron intermediate progenitors (OBIN-IPCs) - a developmental program frequently co-opted in glioblastoma (GBM) to drive tumorigenesis. Here, we show that the transcription factors Olig1/2 coordinately regulate Tri-IPC fate specification through dual transcriptional mechanisms: they activate OPC specification while simultaneously repressing OBIN-IPC generation by directly suppressing Gsx2 expression. Genetic ablation of Olig1/2 redirects Tri-IPCs from producing proliferative OPCs to generating non-proliferative OBIN-IPCs, concomitant with Gsx2 upregulation. Mechanistically, Olig1/2 bind and silence multiple conserved enhancer elements of Gsx2. Remarkably, in proneural GBM models, Olig1/2 deletion reprograms glioma stem cells toward OBIN-IPC-like cells, potently inhibiting tumor growth and improving survival. Integrative multi-omics and immunohistochemical staining analyses further identify cortical Tri-IPCs as the likely cellular origin of human H3.3G34R/V gliomas. These findings establish Olig1/2 as master regulators linking normal gliogenesis to gliomagenesis, and reveal therapeutic opportunities through fate reprogramming of glioma cells.