Autism genes converge on asynchronous development of shared neuron classes.
Autism genes converge on asynchronous development of shared neuron classes.
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DOI：
10.1038/s41586-021-04358-6
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发表时间：
2022-03
期刊：
影响因子：
64.8
通讯作者：
Arlotta P
中科院分区：
文献类型：
--
作者：
Paulsen B;Velasco S;Kedaigle AJ;Pigoni M;Quadrato G;Deo AJ;Adiconis X;Uzquiano A;Sartore R;Yang SM;Simmons SK;Symvoulidis P;Kim K;Tsafou K;Podury A;Abbate C;Tucewicz A;Smith SN;Albanese A;Barrett L;Sanjana NE;Shi X;Chung K;Lage K;Boyden ES;Regev A;Levin JZ;Arlotta P
自闭症谱系障碍 (ASD) 的遗传风险与涵盖广泛生物功能的数百个基因有关。这些基因突变导致的人脑变化仍不清楚。此外，它们的表型表现因个体而异。在这里，我们利用人类大脑皮层的类器官模型，使用超过 745,000 个细胞的单细胞 RNA 测序 (scRNA-seq) 和单个类器官的蛋白质组分析，识别来自不同供体的多个细胞系中三个 ASD 风险基因 SUV420H1 (KMT5B)、ARID1B 和 CHD8 的单倍体不足导致的细胞类型特异性发育异常，以识别表型收敛。这三种突变中的每一种都表明两种主要皮质神经元谱系（GABA能神经元和深层兴奋性投射神经元）的异步发育，但通过很大程度上不同的分子途径发挥作用。尽管这些表型在细胞系中是一致的，但它们的表达量受到个体基因组背景的影响，其方式取决于风险基因和发育缺陷。完整类器官中的钙成像显示，这些早期发育变化之后会出现异常的回路活动。这项工作揭示了 ASD 风险基因所共有的细胞类型特异性神经发育异常，这些异常受到人类基因组背景的精细调节，揭示了不同风险基因如何促进 ASD 病理学的神经生物学基础的趋同。
Genetic risk for autism spectrum disorders (ASD) is associated with hundreds of genes spanning a wide range of biological functions. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals. Here, we leveraged organoid models of the human cerebral cortex to identify cell type-specific developmental abnormalities resulting from haploinsufficiency in three ASD risk genes, SUV420H1 (KMT5B), ARID1B, and CHD8, in multiple cell lines from different donors, using single-cell RNA-seq (scRNA-seq) of over 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations demonstrates asynchronous development of two main cortical neuronal lineages, GABAergic neurons and deep-layer excitatory projection neurons, but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This work uncovers cell type-specific neurodevelopmental abnormalities shared across ASD risk genes that are finely modulated by human genomic context, revealing convergence in the neurobiological basis of how different risk genes contribute to ASD pathology.
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影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
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影响因子：
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Langfelder P;Horvath S
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作者：
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通讯作者：
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4.3
作者：
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Kwee I
影响因子：
12.3
作者：
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通讯作者：
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