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Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex
The EMBO Journal ( IF 9.4 ) Pub Date : 2021-08-25 , DOI: 10.15252/embj.2021108041
Fabio Da Silva 1 , Kaiqing Zhang 1 , Anneline Pinson 2 , Edoardo Fatti 1 , Michaela Wilsch-Bräuninger 2 , Jessica Herbst 1 , Valerie Vidal 3 , Andreas Schedl 3 , Wieland B Huttner 2 , Christof Niehrs 1, 4
Affiliation  

The role of WNT/β-catenin signalling in mouse neocortex development remains ambiguous. Most studies demonstrate that WNT/β-catenin regulates progenitor self-renewal but others suggest it can also promote differentiation. Here we explore the role of WNT/STOP signalling, which stabilizes proteins during G2/M by inhibiting glycogen synthase kinase (GSK3)-mediated protein degradation. We show that mice mutant for cyclin Y and cyclin Y-like 1 (Ccny/l1), key regulators of WNT/STOP signalling, display reduced neurogenesis in the developing neocortex. Specifically, basal progenitors, which exhibit delayed cell cycle progression, were drastically decreased. Ccny/l1-deficient apical progenitors show reduced asymmetric division due to an increase in apical–basal astral microtubules. We identify the neurogenic transcription factors Sox4 and Sox11 as direct GSK3 targets that are stabilized by WNT/STOP signalling in basal progenitors during mitosis and that promote neuron generation. Our work reveals that WNT/STOP signalling drives cortical neurogenesis and identifies mitosis as a critical phase for neural progenitor fate.

中文翻译:


有丝分裂 WNT 信号协调发育中新皮质的神经发生



WNT/β-连环蛋白信号在小鼠新皮质发育中的作用仍然不明确。大多数研究表明 WNT/β-catenin 调节祖细胞自我更新,但其他研究表明它也可以促进分化。在这里,我们探讨了 WNT/STOP 信号传导的作用,它通过抑制糖原合酶激酶 (GSK3) 介导的蛋白质降解来稳定 G2/M 期间的蛋白质。我们发现,细胞周期蛋白 Y 和细胞周期蛋白 Y 样 1 ( Ccny / l1 )(WNT/STOP 信号传导的关键调节因子)的小鼠突变体在发育中的新皮质中表现出神经发生减少。具体来说,表现出细胞周期进程延迟的基础祖细胞急剧减少。 Ccny / l1缺陷的顶端祖细胞由于顶端-基底星形微管的增加而表现出不对称分裂减少。我们将神经源性转录因子 Sox4 和 Sox11 确定为 GSK3 的直接靶标,它们在有丝分裂期间通过基底祖细胞中的 WNT/STOP 信号稳定,并促进神经元生成。我们的工作揭示了 WNT/STOP 信号传导驱动皮质神经发生,并将有丝分裂确定为神经祖细胞命运的关键阶段。
更新日期:2021-10-04
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