Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids.
Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids.
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DOI：
10.1038/s41467-023-39420-6
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发表时间：
2023-06-24
影响因子：
16.6
通讯作者：
Pak, ChangHui
中科院分区：
文献类型：
--
作者：
Sebastian, Rebecca;Jin, Kang;Pavon, Narciso;Bansal, Ruby;Potter, Andrew;Song, Yoonjae;Babu, Juliana;Gabriel, Rafael;Sun, Yubing;Aronow, Bruce;Pak, ChangHui
NRXN1 （2p16.3）的新生突变和拷贝数缺失对精神分裂症（SCZ）有显著的风险。目前尚不清楚NRXN1缺失如何以细胞类型特异性的方式影响皮质发育，以及疾病背景如何调节这些表型。在这里，我们利用人类多能干细胞衍生的前脑类器官模型，在等基因和SCZ患者遗传背景下携带NRXN1杂合缺失，并在3周到3.5个月的脑类器官发育过程中进行单细胞转录组学分析。有趣的是，虽然这两种缺失都类似地影响了与泛素-蛋白酶体系统、替代剪接和成熟谷氨酸能和gaba能神经元突触信号相关的分子通路，但SCZ-NRXN1缺失特异性地干扰了早期神经祖细胞的发育轨迹和积累疾病特异性转录组特征。通过钙成像，我们发现这两种缺失导致自发和同步神经元网络的长期变化，暗示突触功能障碍。我们的研究揭示了NRXN1缺失在独特遗传背景下的发育时间和细胞类型依赖作用。个体2p16.3位点（NRXN1）拷贝数缺失显著增加患精神分裂症的风险。在这里，作者展示了，在单细胞水平上，遗传背景特异性作用最终导致突触功能障碍，使用ipsc衍生的脑类器官模型。
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. Copy number deletions in 2p16.3 locus (NRXN1) in individuals significantly increase risk for schizophrenia. Here, authors show, at single cell level, genetic background-specific effects that culminate in synaptic dysfunction using iPSC-derived brain organoid model.
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影响因子：
64.8
作者：
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通讯作者：
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影响因子：
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作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
通讯作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
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影响因子：
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作者：
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Ozaki N
影响因子：
23.9
作者：
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通讯作者：
Kriegstein AR
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影响因子：
56.9
作者：
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通讯作者：
Geschwind, Daniel H.