2023/09/29
论文
论文标题：Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment
作者：Meng, Xiangling, Yao, David, Imaizumi, Kent, Chen, Xiaoyu, Kelley, Kevin W., Reis, Noah, Thete, Mayuri Vijay, Arjun McKinney, Arpana, Kulkarni, Shravanti, Panagiotakos, Georgia, Bassik, Michael C., Pașca, Sergiu P.
期刊：Nature
发表时间：2023/09/27
数字识别码：10.1038/s41586-023-06564-w
摘要：The assembly of cortical circuits involves the generation and migration of interneurons from the ventral to the dorsal forebrain1,2,3, which has been challenging to study at inaccessible stages of late gestation and early postnatal human development4. Autism spectrum disorder and other neurodevelopmental disorders (NDDs) have been associated with abnormal cortical interneuron development5, but which of these NDD genes affect interneuron generation and migration, and how they mediate these effects remains unknown. We previously developed a platform to study interneuron development and migration in subpallial organoids and forebrain assembloids6. Here we integrate assembloids with CRISPR screening to investigate the involvement of 425 NDD genes in human interneuron development. The first screen aimed at interneuron generation revealed 13 candidate genes, including CSDE1 and SMAD4. We subsequently conducted an interneuron migration screen in more than 1,000 forebrain assembloids that identified 33 candidate genes, including cytoskeleton-related genes and the endoplasmic reticulum-related gene LNPK. We discovered that, during interneuron migration, the endoplasmic reticulum is displaced along the leading neuronal branch before nuclear translocation. LNPK deletion interfered with this endoplasmic reticulum displacement and resulted in abnormal migration. These results highlight the power of this CRISPR-assembloid platform to systematically map NDD genes onto human development and reveal disease mechanisms.
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摘要翻译（由计算机程序完成，仅供参考，内容以英文原文为准）：
皮层回路的组装涉及中间神经元从腹侧前脑1，2，3的产生和迁移，这在妊娠晚期和出生后早期人类发育的难以接近的阶段一直具有挑战性4。自闭症谱系障碍和其他神经发育障碍（NDD）与皮质中间神经元发育异常有关5，但这些NDD基因中的哪些影响中间神经元的生成和迁移，以及它们如何介导这些影响尚不清楚。我们之前开发了一个平台来研究中间神经元在亚球形类器官和前脑组件中的发育和迁移6。在这里，我们将组装体与CRISPR筛选相结合，以研究425个NDD基因在人类中间神经元发育中的作用。第一次针对中间神经元生成的筛选揭示了13个候选基因，包括CSDE1和SMAD4。随后，我们在1000多个前脑组装体中进行了中间神经元迁移筛选，确定了33个候选基因，包括细胞骨架相关基因和内质网相关基因LNPK。我们发现，在中间神经元迁移过程中，内质网在细胞核移位之前沿着主要的神经元分支移位。LNPK缺失干扰了这种内质网移位并导致异常迁移。这些结果突出了这种CRISPR组装体平台系统地将NDD基因映射到人类发育和揭示疾病机制的能力。
参考资料：
[1] Meng, X., Yao, D., Imaizumi, K. et al. Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment. Nature (2023). https://doi.org/10.1038/s41586-023-06564-w
