During neocortical development, neural stem cells (NSCs) divide symmetrically to self-renew at the early stage and then divide asymmetrically to generate post-mitotic neurons. The molecular mechanisms regulating the balance between NSC self-renewal and neurogenesis are not fully understood. Using mouse in utero electroporation (IUE) technique and in vitro human NSC differentiation models including cerebral organoids (hCOs), we show here that regulator of cell cycle (RGCC) modulates NSC self-renewal and neuronal differentiation by affecting cell cycle regulation and spindle orientation. RGCC deficiency hampers normal cell cycle process and dysregulates the mitotic spindle, thus driving more cells to divide asymmetrically. These modulations diminish the NSC population and cause NSC pre-differentiation that eventually leads to brain developmental malformation in hCOs. We further show that RGCC might regulate NSC spindle orientation by affecting the organization of centrosome and microtubules. Our results demonstrate that RGCC is essential to maintain the NSC pool during cortical development and suggest that RGCC defects could have etiological roles in human brain malformations.

中文翻译：

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RGCC 平衡发育中的哺乳动物新皮质中神经干细胞的自我更新和神经元分化

在新皮质发育过程中，神经干细胞 (NSC) 在早期对称分裂以自我更新，然后不对称分裂以产生有丝分裂后的神经元。调节 NSC 自我更新和神经发生之间平衡的分子机制尚不完全清楚。使用小鼠子宫内电穿孔 (IUE) 技术和体外人类 NSC 分化模型，包括脑类器官 (hCOs)，我们在此表明​​细胞周期调节剂 ( RGCC ) 通过影响细胞周期调节和纺锤体方向来调节 NSC 自我更新和神经元分化. RGCC缺乏会阻碍正常的细胞周期过程并失调有丝分裂纺锤体，从而驱动更多的细胞不对称分裂。这些调节减少了 NSC 种群并导致 NSC 预分化，最终导致 hCO 中的大脑发育畸形。我们进一步表明，RGCC可能通过影响中心体和微管的组织来调节 NSC 纺锤体的方向。我们的研究结果表明，RGCC对于在皮质发育过程中维持 NSC 池至关重要，并表明RGCC缺陷可能在人脑畸形中具有病因学作用。