Cell-type specific defects in PTEN-mutant cortical organoids converge on abnormal circuit activity.
Cell-type specific defects in PTEN-mutant cortical organoids converge on abnormal circuit activity.
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DOI：
10.1093/hmg/ddad107
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发表时间：
2023-06
影响因子：
3.5
通讯作者：
Martina Pigoni;Ana Uzquiano;B. Paulsen;Amanda J. Kedaigle;S. M. Yang;Panagiotis Symvoulidis;Xian Adiconis;Silvia Velasco;R. Sartore;Kwanho Kim;Ashley Tucewicz;Sarah Yoshimi Tropp;K. Tsafou;Xin Jin;L. Barrett;Fei Chen;Edwatrd S. Boyden;A. Regev;J. Levin;P. Arlotta
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文献类型：
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作者：
Martina Pigoni;Ana Uzquiano;B. Paulsen;Amanda J. Kedaigle;S. M. Yang;Panagiotis Symvoulidis;Xian Adiconis;Silvia Velasco;R. Sartore;Kwanho Kim;Ashley Tucewicz;Sarah Yoshimi Tropp;K. Tsafou;Xin Jin;L. Barrett;Fei Chen;Edwatrd S. Boyden;A. Regev;J. Levin;P. Arlotta
PTEN的从头杂合功能丧失突变与自闭症谱系障碍（ASD）密切相关；然而，目前尚不清楚该基因的杂合突变如何影响人类大脑发育过程中的不同细胞类型，以及这些影响在个体之间如何变化。在这里，我们使用来自不同供体的人类皮质类器官来鉴定受PTEN杂合突变影响的细胞类型特异性发育事件。我们通过单细胞RNA-seq，蛋白质组学和空间转录组学分析了个体类器官，并揭示了人类外放射状胶质祖细胞和深层皮层投射神经元的发育时间异常，其随供体遗传背景而变化。完整类器官的钙成像显示，无论遗传背景如何，加速和延迟的神经元发育表型都会导致相似的局部电路异常活动。这项工作揭示了PTEN杂合性的供体依赖性、细胞型特异性发育表型，这些表型后来集中在被破坏的神经元活动上。
De novo heterozygous loss-of-function mutations in PTEN are strongly associated with Autism spectrum disorders (ASD); however, it is unclear how heterozygous mutations in this gene affects different cell types during human brain development, and how these effects vary across individuals. Here, we used human cortical organoids from different donors to identify cell-type-specific developmental events that are affected by heterozygous mutations in PTEN. We profiled individual organoids by single-cell RNA-seq, proteomics, and spatial transcriptomics, and revealed abnormalities in developmental timing in human outer radial glia progenitors and deep layer cortical projection neurons, which varied with the donor genetic background. Calcium imaging in intact organoids showed that both accelerated and delayed neuronal development phenotypes resulted in similar abnormal activity of local circuits, irrespective of genetic background. The work reveals donor-dependent, cell-type specific developmental phenotypes of PTEN heterozygosity that later converge on disrupted neuronal activity.