CYCLIN-B1/2 and-D1 act in opposition to coordinate cortical progenitor self-renewal and lineage commitment
CYCLIN-B1/2 and-D1 act in opposition to coordinate cortical progenitor self-renewal and lineage commitment
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DOI：
10.1038/s41467-020-16597-8
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发表时间：
2020-06-09
影响因子：
16.6
通讯作者：
Muhr, Jonas
中科院分区：
文献类型：
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作者：
Hagey, Daniel W.;Topcic, Danijal;Muhr, Jonas
层特异性皮层神经元的连续生成需要放射状胶质细胞（RGC）精确地平衡自我更新和谱系承诺。虽然特定的细胞周期阶段已与这些决定，连接细胞周期机制的细胞命运的承诺仍然模糊。使用单细胞RNA测序，我们发现定义多能RGCs的最强转录特征是G2/M期，特别是CYP 1A-B1/2，而谱系定型祖细胞富含G1/S期基因，包括CYP 1A-D1。这些数据还揭示了细胞表面标志物，使我们能够分离RGCs和谱系定型祖细胞，并在功能上证实细胞周期阶段富集和细胞命运能力之间的关系。最后，我们使用皮层电穿孔来证明CYP 1A-B1/2与CDK 1合作通过激活NOTCH通路来维持未定型的RGCs，并且CYP 1A-D1促进分化。因此，这项工作确立了细胞周期阶段特异性调节剂通过核心干细胞调节途径相反地协调RGCs的自我更新和谱系承诺。层特异性皮质神经元的顺序生成需要放射状胶质细胞（RGC）来平衡自我更新和承诺。在这里，作者表明，RGCs和谱系定向祖细胞由不同的细胞周期阶段定义，CYP 1A-B1/2与CDK 1合作激活Notch并维持RGCs。
The sequential generation of layer-specific cortical neurons requires radial glia cells (RGCs) to precisely balance self-renewal and lineage commitment. While specific cell-cycle phases have been associated with these decisions, the mechanisms linking the cell-cycle machinery to cell-fate commitment remain obscure. Using single-cell RNA-sequencing, we find that the strongest transcriptional signature defining multipotent RGCs is that of G2/M-phase, and particularly CYCLIN-B1/2, while lineage-committed progenitors are enriched in G1/S-phase genes, including CYCLIN-D1. These data also reveal cell-surface markers that allow us to isolate RGCs and lineage-committed progenitors, and functionally confirm the relationship between cell-cycle phase enrichment and cell fate competence. Finally, we use cortical electroporation to demonstrate that CYCLIN-B1/2 cooperate with CDK1 to maintain uncommitted RGCs by activating the NOTCH pathway, and that CYCLIN-D1 promotes differentiation. Thus, this work establishes that cell-cycle phase-specific regulators act in opposition to coordinate the self-renewal and lineage commitment of RGCs via core stem cell regulatory pathways. Sequential generation of layer-specific cortical neurons requires radial glial cells (RGCs) to balance self-renewal and commitment. Here the authors show that RGCs and lineage committed progenitors are defined by distinct cell cycle phases and CYCLIN-B1/2 cooperates with CDK1 to activate Notch and maintain RGCs.