Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment

Xiangling Meng, David Yao, Kent Imaizumi, Xiaoyu Chen, Kevin W. Kelley, Noah Reis, Mayuri Vijay Thete, Arpana Arjun McKinney, Shravanti Kulkarni, Georgia Panagiotakos, Michael C. Bassik and Sergiu P. Pașca ()
Additional contact information
Xiangling Meng: Stanford University
David Yao: Stanford University
Kent Imaizumi: Stanford University
Xiaoyu Chen: Stanford University
Kevin W. Kelley: Stanford University
Noah Reis: Stanford University
Mayuri Vijay Thete: Stanford University
Arpana Arjun McKinney: University of California
Shravanti Kulkarni: Stanford University
Georgia Panagiotakos: University of California
Michael C. Bassik: Stanford University
Sergiu P. Pașca: Stanford University

Nature, 2023, vol. 622, issue 7982, 359-366

Abstract: Abstract The assembly of cortical circuits involves the generation and migration of interneurons from the ventral to the dorsal forebrain1–3, 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.

Date: 2023
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DOI: 10.1038/s41586-023-06564-w

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