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Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids

De novo mutations and copy number deletions in NRXN1 (2p16.3) pose a significant risk for schizophrenia (SCZ). It is unclear how NRXN1 deletions impact cortical development in a cell type-specific manner and disease background modulates these phenotypes. Here, we leveraged human pluripotent stem cel...

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Autores principales: Sebastian, Rebecca, Jin, Kang, Pavon, Narciso, Bansal, Ruby, Potter, Andrew, Song, Yoonjae, Babu, Juliana, Gabriel, Rafael, Sun, Yubing, Aronow, Bruce, Pak, ChangHui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10290702/
https://www.ncbi.nlm.nih.gov/pubmed/37355690
http://dx.doi.org/10.1038/s41467-023-39420-6
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author Sebastian, Rebecca
Jin, Kang
Pavon, Narciso
Bansal, Ruby
Potter, Andrew
Song, Yoonjae
Babu, Juliana
Gabriel, Rafael
Sun, Yubing
Aronow, Bruce
Pak, ChangHui
author_facet Sebastian, Rebecca
Jin, Kang
Pavon, Narciso
Bansal, Ruby
Potter, Andrew
Song, Yoonjae
Babu, Juliana
Gabriel, Rafael
Sun, Yubing
Aronow, Bruce
Pak, ChangHui
author_sort Sebastian, Rebecca
collection PubMed
description De novo mutations and copy number deletions in NRXN1 (2p16.3) pose a significant risk for schizophrenia (SCZ). It is unclear how NRXN1 deletions impact cortical development in a cell type-specific manner and disease background modulates these phenotypes. Here, we leveraged human pluripotent stem cell-derived forebrain organoid models carrying NRXN1 heterozygous deletions in isogenic and SCZ patient genetic backgrounds and conducted single-cell transcriptomic analysis over the course of brain organoid development from 3 weeks to 3.5 months. Intriguingly, while both deletions similarly impacted molecular pathways associated with ubiquitin-proteasome system, alternative splicing, and synaptic signaling in maturing glutamatergic and GABAergic neurons, SCZ-NRXN1 deletions specifically perturbed developmental trajectories of early neural progenitors and accumulated disease-specific transcriptomic signatures. Using calcium imaging, we found that both deletions led to long-lasting changes in spontaneous and synchronous neuronal networks, implicating synaptic dysfunction. Our study reveals developmental-timing- and cell-type-dependent actions of NRXN1 deletions in unique genetic contexts.
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spelling pubmed-102907022023-06-26 Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids Sebastian, Rebecca Jin, Kang Pavon, Narciso Bansal, Ruby Potter, Andrew Song, Yoonjae Babu, Juliana Gabriel, Rafael Sun, Yubing Aronow, Bruce Pak, ChangHui Nat Commun Article De novo mutations and copy number deletions in NRXN1 (2p16.3) pose a significant risk for schizophrenia (SCZ). It is unclear how NRXN1 deletions impact cortical development in a cell type-specific manner and disease background modulates these phenotypes. Here, we leveraged human pluripotent stem cell-derived forebrain organoid models carrying NRXN1 heterozygous deletions in isogenic and SCZ patient genetic backgrounds and conducted single-cell transcriptomic analysis over the course of brain organoid development from 3 weeks to 3.5 months. Intriguingly, while both deletions similarly impacted molecular pathways associated with ubiquitin-proteasome system, alternative splicing, and synaptic signaling in maturing glutamatergic and GABAergic neurons, SCZ-NRXN1 deletions specifically perturbed developmental trajectories of early neural progenitors and accumulated disease-specific transcriptomic signatures. Using calcium imaging, we found that both deletions led to long-lasting changes in spontaneous and synchronous neuronal networks, implicating synaptic dysfunction. Our study reveals developmental-timing- and cell-type-dependent actions of NRXN1 deletions in unique genetic contexts. Nature Publishing Group UK 2023-06-24 /pmc/articles/PMC10290702/ /pubmed/37355690 http://dx.doi.org/10.1038/s41467-023-39420-6 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sebastian, Rebecca
Jin, Kang
Pavon, Narciso
Bansal, Ruby
Potter, Andrew
Song, Yoonjae
Babu, Juliana
Gabriel, Rafael
Sun, Yubing
Aronow, Bruce
Pak, ChangHui
Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids
title Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids
title_full Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids
title_fullStr Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids
title_full_unstemmed Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids
title_short Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids
title_sort schizophrenia-associated nrxn1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10290702/
https://www.ncbi.nlm.nih.gov/pubmed/37355690
http://dx.doi.org/10.1038/s41467-023-39420-6
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