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Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment

The assembly of cortical circuits involves the generation and migration of interneurons from the ventral to the dorsal forebrain(1–3), which has been challenging to study at inaccessible stages of late gestation and early postnatal human development(4). Autism spectrum disorder and other neurodevelo...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10567561/
https://www.ncbi.nlm.nih.gov/pubmed/37758944
http://dx.doi.org/10.1038/s41586-023-06564-w
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author 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.
author_facet 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.
author_sort Meng, Xiangling
collection PubMed
description The assembly of cortical circuits involves the generation and migration of interneurons from the ventral to the dorsal forebrain(1–3), which has been challenging to study at inaccessible stages of late gestation and early postnatal human development(4). Autism spectrum disorder and other neurodevelopmental disorders (NDDs) have been associated with abnormal cortical interneuron development(5), 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 assembloids(6). 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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spelling pubmed-105675612023-10-13 Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment 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. Nature Article The assembly of cortical circuits involves the generation and migration of interneurons from the ventral to the dorsal forebrain(1–3), which has been challenging to study at inaccessible stages of late gestation and early postnatal human development(4). Autism spectrum disorder and other neurodevelopmental disorders (NDDs) have been associated with abnormal cortical interneuron development(5), 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 assembloids(6). 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. Nature Publishing Group UK 2023-09-27 2023 /pmc/articles/PMC10567561/ /pubmed/37758944 http://dx.doi.org/10.1038/s41586-023-06564-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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.
Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment
title Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment
title_full Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment
title_fullStr Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment
title_full_unstemmed Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment
title_short Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment
title_sort assembloid crispr screens reveal impact of disease genes in human neurodevelopment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10567561/
https://www.ncbi.nlm.nih.gov/pubmed/37758944
http://dx.doi.org/10.1038/s41586-023-06564-w
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