Cyclin-dependent kinase inhibitor p18 regulates lineage transitions of excitatory neurons, astrocytes, and interneurons in the mouse cortex.

IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Wonyoung Lee, Byunghee Kang, Hyo-Min Kim, Tsuyoshi Ishida, Minkyung Shin, Misato Iwashita, Masahiro Nitta, Aki Shiraishi, Hiroshi Kiyonari, Koichiro Shimoya, Kazuto Masamoto, Tae-Young Roh, Yoichi Kosodo
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引用次数: 0

Abstract

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.

细胞周期蛋白依赖性激酶抑制剂p18调控小鼠大脑皮层兴奋性神经元、星形胶质细胞和中间神经元的谱系转换
神经干细胞(NSCs)既能产生神经元,也能产生胶质细胞,但对其分化转换的调控机制仍不完全清楚。在这里,我们探讨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阶段的作用。我们发现,CDKIs p18 和 p27 在星形胶质细胞开始生成时上调。对 p18 和 p27 水平的急性操作显示,CDKIs 在过渡阶段可调节上层神经元和星形胶质细胞之间的谱系转换。我们建立了一个条件性基因敲入小鼠模型来诱导 NSCs 中的 p18。显微解剖组织的转录组解构显示,p18 水平的升高会促进胶质细胞的发育并激活 Delta-Notch 信号转导。此外,我们还发现 p18 能上调同源转录因子 Dlx2,从而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。利用转座子报告基因进行的克隆分析表明,在单细胞水平上,p18能促进从星形胶质细胞向中间神经元的过渡。总之,我们的研究报告了 p18 在决定背侧皮层中由 NSCs 依次产生的不同细胞系之间的发育边界方面的功能。
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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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