Department of Anesthesia, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, and Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Laboratory of Epi-Informatics, Intelligent Medicine Institute of Fudan University, Shanghai, 200032, China.
EMBO J. 2024 Nov;43(21):5114-5140. doi: 10.1038/s44318-024-00218-x. Epub 2024 Sep 19.
Astrocytes in the brain exhibit regional heterogeneity contributing to regional circuits involved in higher-order brain functions, yet the mechanisms controlling their distribution remain unclear. Here, we show that the precise allocation of astrocytes to specific brain regions during development is achieved through transcription factor 4 (Tcf4)-mediated fate restriction based on their embryonic origin. Loss of Tcf4 in ventral telencephalic neural progenitor cells alters the fate of oligodendrocyte precursor cells to transient intermediate astrocyte precursor cells, resulting in mislocalized astrocytes in the dorsal neocortex. These ectopic astrocytes engage with neocortical neurons and acquire features reminiscent of dorsal neocortical astrocytes. Furthermore, Tcf4 functions as a suppressor of astrocyte fate during the differentiation of oligodendrocyte precursor cells derived from the ventral telencephalon, thereby restricting the fate to the oligodendrocyte lineage in the dorsal neocortex. Together, our findings highlight a previously unappreciated role for Tcf4 in regulating astrocyte allocation, offering additional insights into the mechanisms underlying neurodevelopmental disorders linked to Tcf4 mutations.
大脑中的星形胶质细胞表现出区域异质性，有助于参与高级脑功能的区域回路，但控制其分布的机制仍不清楚。在这里，我们表明，星形胶质细胞在发育过程中精确分配到特定脑区是通过转录因子 4（Tcf4）介导的基于其胚胎起源的命运限制来实现的。腹侧端脑神经祖细胞中 Tcf4 的缺失改变了少突胶质前体细胞的命运为短暂的中间星形胶质前体细胞，导致背侧新皮层中出现定位错误的星形胶质细胞。这些异位星形胶质细胞与新皮层神经元相互作用，并获得类似于背侧新皮层星形胶质细胞的特征。此外，Tcf4 在源自腹侧端脑的少突胶质前体细胞分化过程中作为星形胶质细胞命运的抑制因子发挥作用，从而将命运限制在背侧新皮层中的少突胶质细胞谱系中。总之，我们的研究结果强调了 Tcf4 在调节星形胶质细胞分配中的先前未被认识的作用，为与 Tcf4 突变相关的神经发育障碍的机制提供了更多的见解。
