Neuronal lineage tracing from progenitors in human cortical organoids reveals novel mechanisms of human neuronal production, diversity, and disease.
Neuronal lineage tracing from progenitors in human cortical organoids reveals novel mechanisms of human neuronal production, diversity, and disease.
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人类皮质类器官祖细胞的神经元谱系追踪揭示了人类神经元产生、多样性和疾病的新机制。
DOI：
10.1101/2023.06.17.545314
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Wynshaw-Boris,Anthony
中科院分区：
文献类型：
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作者：
Bury,LukeAD;Fu,Shuai;Wynshaw-Boris,Anthony
在人类皮层神经发生过程中，祖细胞亚型对产生数十亿神经元的贡献尚不清楚。我们为人类皮质类器官开发了皮质类器官谱系追踪（COR-LT）系统。不同祖细胞中的差异荧光报告子激活导致永久报告子表达，使得能够确定神经元的祖细胞谱系。令人惊讶的是，几乎所有在皮质类器官中产生的神经元都是从中间祖细胞间接产生的。此外，不同祖细胞谱系的神经元在转录上是不同的。从CTNNB 1基因中具有和不具有可能的致病性变体的自闭症个体制成的等基因系表明，该变体实质上改变了来自特定祖细胞谱系的神经元的比例，以及这些神经元的谱系特异性转录谱，表明这种突变的致病机制。这些结果表明，个体祖细胞亚型在产生人类大脑皮层的不同神经元中发挥着独特的作用。
The contribution of progenitor subtypes to generate the billions of neurons during human cortical neurogenesis is not well understood. We developed the Cortical ORganoid Lineage Tracing (COR-LT) system for human cortical organoids. Differential fluorescent reporter activation in distinct progenitor cells leads to permanent reporter expression, enabling the progenitor cell lineage of neurons to be determined. Surprisingly, nearly all neurons produced in cortical organoids were generated indirectly from intermediate progenitor cells. Additionally, neurons of different progenitor lineages were transcriptionally distinct. Isogenic lines made from an autistic individual with and without a likely pathogenic variant in the CTNNB1 gene demonstrated that the variant substantially altered the proportion of neurons derived from specific progenitor cell lineages, as well as the lineage-specific transcriptional profiles of these neurons, suggesting a pathogenic mechanism for this mutation. These results suggest individual progenitor subtypes play unique roles in generating the diverse neurons of the human cerebral cortex.Graphic Abstract