Olig1/2 Orchestrates Progenitor Cell Fates during Mammalian Cortical Gliogenesis and Gliomagenesis

作者：Yu Tian, Zi‐Wu Wang, Feihong Yang, Wen Zhang, Jialin Li, Lin Yang, Tao Fu, Wenhui Zheng, Zhejun Xu, Tong Ma, Yan You, Xiaosu Li, Jiangang Song, Yunli Xie, Zhengang Yang, Zhuangzhi Zhang · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-64753-9 · 被引用次数：7 · 研究领域：Neurogenesis and neuroplasticity mechanisms、Glioma Diagnosis and Treatment、Pluripotent Stem Cells Research

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. Developmental programs are frequently co-opted in glioblastoma. Here, the authors show the role of transcription factors Olig1/2 in fate specification of tri-potential interme...