NOTCH, ERK and SHH signaling respectively control the fate determination of cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons

During cortical development, radial glial cells, known as neural stem cells, initially generate a large number of cortical glutamatergic pyramidal neurons through a process called neurogenesis. This is followed by the generation of a diversity of cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons, known as gliogenesis. However, the molecular mechanisms underlying the switch 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 cortical glial progenitors. Additionally, SHH-SMO-GLI activator signaling has an auxiliary function to ERK during these processes. We further demonstrate that NOTCH signaling is absolutely required for the fate determination of astrocytes, while ERK signaling plays a prominent role in oligodendrocyte fate specification, and SHH signaling is crucial for the fate determination of olfactory bulb interneurons from cortical progenitors. We provide evidence suggesting that this mechanism is conserved in both mice and humans. Finally, we propose a unifying principle of mammalian cortical gliogenesis.在大脑皮层发育过程中，放射状胶质细胞（radial glial cells）又被称为神经干细胞（neural stem cells），最初会通过神经发生（neurogenesis）过程生成大量的皮层谷氨酸能锥体神经元。随后，它们会通过胶质发生（gliogenesis）过程产生多种皮层星形胶质细胞（astrocytes）、少突胶质细胞（oligodendrocytes）以及嗅球中间神经元（olfactory bulb interneurons）。然而，皮层神经发生向胶质发生转变的分子机制，以及皮层星形胶质细胞、少突胶质细胞与嗅球中间神经元的后续命运决定机制，目前仍未阐明。本研究证实，细胞外信号调节激酶（extracellular signal-regulated kinase, ERK）信号通路在促进皮层胶质发生以及皮层胶质祖细胞生成方面发挥着核心作用。此外，SHH-SMO-GLI激活信号通路（SHH-SMO-GLI activator signaling）在上述过程中对ERK信号通路具有辅助调控功能。我们进一步证实，Notch信号通路（NOTCH signaling）是星形胶质细胞命运决定所绝对必需的；ERK信号通路在少突胶质细胞命运特化过程中发挥关键调控作用；而SHH信号通路对于皮层祖细胞向嗅球中间神经元的命运决定至关重要。本研究提供的证据表明，该机制在小鼠与人类中均具有进化保守性。最后，我们提出了哺乳动物皮层胶质发生的统一调控原则。