Neural stem cells (NSCs) can give rise to both neurons and glia, but the regulatory mechanisms governing their differentiation transitions remain incompletely understood. Here, we address the role of cyclin-dependent kinase inhibitors (CDKIs) in the later stages of dorsal cortical development. We find that the CDKIs p18 and p27 are upregulated at the onset of astrocyte generation. Acute manipulation of p18 and p27 levels shows that CDKIs modulate lineage switching between upper-layer neurons and astrocytes at the transitional stage. We generate a conditional knock-in mouse model to induce p18 in NSCs. The transcriptomic deconvolution of microdissected tissue reveals that increased levels of p18 promote glial cell development and activate Delta-Notch signaling. Furthermore, we show that p18 upregulates the homeobox transcription factor Dlx2 to subsequently induce the differentiation of olfactory bulb interneurons while reducing the numbers of upper-layer neurons and astrocytes at the perinatal stage. Clonal analysis using transposon-based reporters reveals that the transition from the astrocyte to the interneuron lineage is potentiated by p18 at the single-cell level. In sum, our study reports a function of p18 in determining the developmental boundaries among different cellular lineages arising sequentially from NSCs in the dorsal cortex.

中文翻译：

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细胞周期蛋白依赖性激酶抑制剂 p18 调节小鼠皮层中兴奋性神经元、星形胶质细胞和中间神经元的谱系转换。


神经干细胞 （NSC） 可以产生神经元和神经胶质细胞，但控制其分化转变的调节机制仍不完全清楚。在这里，我们讨论了细胞周期蛋白依赖性激酶抑制剂 （CDKIs） 在背侧皮层发育后期的作用。我们发现 CDKI p18 和 p27 在星形胶质细胞生成开始时上调。p18 和 p27 水平的急性操作表明，CDKI 在过渡阶段调节上层神经元和星形胶质细胞之间的谱系转换。我们生成了一个条件性敲入小鼠模型来诱导 NSC 中的 p18。显微解剖组织的转录组反卷积显示，p18 水平升高可促进神经胶质细胞发育并激活 Delta-Notch 信号传导。此外，我们表明 p18 上调同源框转录因子 Dlx2 以随后诱导嗅球中间神经元的分化，同时减少围产期上层神经元和星形胶质细胞的数量。使用基于转座子的报告基因的克隆分析表明，p18 在单细胞水平上增强了从星形胶质细胞到神经元间谱系的转变。总之，我们的研究报告了 p18 在确定背皮层 NSC 依次产生的不同细胞谱系之间的发育边界方面的作用。