Gao Yanjing, Sun Mengge, Fu Tongye, Wang Ziwu, Jiang Xin, Yang Lin, Liang Xiaoyi G, Liu Guoping, Tian Yu, Yang Feihong, Li Jialin, Li Zhenmeiyu, Li Xiaosu, You Yan, Ding Chaoqiong, Wang Yuan, Ma Tong, Zhang Zhuangzhi, Xu Zhejun, Chen Bin, Yang Zhengang
Department of Neurology, Zhongshan Hospital, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China.
Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064.
Proc Natl Acad Sci U S A. 2025 Mar 4;122(9):e2416757122. doi: 10.1073/pnas.2416757122. Epub 2025 Feb 25.
During cortical development, radial glial cells (neural stem cells) initially are neurogenic, generating intermediate progenitor cells that exclusively produce glutamatergic pyramidal neurons. Next, radial glial cells generate tripotential intermediate progenitor cells (Tri-IPCs) that give rise to cortical astrocytes and oligodendrocytes, and olfactory bulb interneurons. The molecular mechanisms underlying the transition from cortical neurogenesis to gliogenesis, and the subsequent fate determination of cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons, remain unclear. Here, we report that extracellular signal-regulated kinase (ERK) signaling plays a fundamental role in promoting cortical gliogenesis and the generation of Tri-IPCs. Additionally, sonic hedgehog-smoothened-glioma-associated oncogene homolog (SHH-SMO-GLI) activator signaling has an auxiliary function to ERK during these processes. We further demonstrate that, from Tri-IPCs, NOTCH signaling is crucial for the fate determination of astrocytes, while ERK signaling plays a prominent role in oligodendrocyte fate specification, and SHH signaling is required for the fate determination of olfactory bulb interneurons. We provide evidence suggesting that this mechanism is conserved in both mice and humans. Finally, we propose a unifying principle of mammalian cortical gliogenesis.
在皮质发育过程中，放射状胶质细胞（神经干细胞）最初具有神经源性，可产生专门生成谷氨酸能锥体神经元的中间祖细胞。接下来，放射状胶质细胞产生三能中间祖细胞（Tri-IPC），后者可分化为皮质星形胶质细胞、少突胶质细胞和嗅球中间神经元。从皮质神经发生向胶质发生转变以及随后皮质星形胶质细胞、少突胶质细胞和嗅球中间神经元命运决定的分子机制仍不清楚。在此，我们报告细胞外信号调节激酶（ERK）信号在促进皮质胶质发生和Tri-IPC生成中起基本作用。此外，在这些过程中，音猬因子-平滑受体-胶质瘤相关癌基因同源物（SHH-SMO-GLI）激活信号对ERK具有辅助作用。我们进一步证明，从Tri-IPC开始，NOTCH信号对星形胶质细胞的命运决定至关重要，而ERK信号在少突胶质细胞命运特化中起突出作用，SHH信号是嗅球中间神经元命运决定所必需的。我们提供的证据表明，这一机制在小鼠和人类中都是保守的。最后，我们提出了哺乳动物皮质胶质发生的统一原理。
