精神分裂症（SCZ）具有已知的神经发育病因，但对于人类胎儿脑组织的有限获取限制了对早期脑发育中基础疾病机制的研究。在这里，我们阐明了在与疾病相关的人类胎儿脑的疾病模型中导致SCZ风险的分子机制。我们利用大规模且基因分层的样本，从14名SCZ患者和14名年龄和性别匹配的对照组（CTRL）中生成了诱导多能干细胞分化的皮质团块（hCSs）。hCSs在150天内分化，并进行了四个时间点的全面分子特征分析。hCSs的转录和细胞结构与10-24胚胎周年龄的大脑非常相似，与大脑额叶区域显示最强的空间重叠。在hCS的所有阶段，SCZ和CTRL hCSs之间共有3,520个基因发生差异调控，其中显示了遗传负荷的显著贡献，自闭症谱系障碍和SCZ的风险基因过表达，以及所有hCS阶段中轴突过程的最强丰富。两个轴突导向基因SEMA7A和SEMA5A，前者是突触功能的促进剂，后者是抑制剂，在SCZ hCSs中分别下调和上调表达。这种表达模式在蛋白质水平上得到确认并在大规模尸体样本中得到复制。通过应用与疾病相关的发育中胎儿脑模型，我们确定了轴突基因的持续失调作为SCZ的早期风险因素，为遗传易感性对障碍的神经发育起源产生了新的认识。版权所有 © 2023 Elsevier Inc. 发布

Schizophrenia (SCZ) has a known neurodevelopmental etiology, but limited access to human prenatal brain tissue hampers the investigation of basic disease mechanisms in early brain development. Here, we elucidate the molecular mechanisms contributing to SCZ risk in a disease-relevant model of the prenatal human brain.We generated induced pluripotent stem cell-derived cortical spheroids (hCSs) from a large and genetically stratified sample of 14 SCZ patients and 14 age and sex-matched controls (CTRL). The hCSs were differentiated for 150 days, and comprehensive molecular characterization across four time points was carried out.The transcriptional and cellular architecture of hCSs closely resembled that of 10-24 post-conception week fetal brain, showing strongest spatial overlap with frontal regions of the cerebral cortex. A total of 3,520 genes were differentially modulated between SCZ and CTRL hCSs across organoid maturation, displaying a significant contribution of genetic loading, an over-representation of risk genes for autism spectrum disorder and SCZ, and strongest enrichment for axonal processes in all hCS stages. The two axon guidance genes SEMA7A and SEMA5A, the first a promoter of synaptic functions and the second a repressor, were down and up-regulated in SCZ hCSs, respectively. This expression pattern was confirmed at the protein level and replicated in a large post-mortem sample.Applying a disease-relevant model of the developing fetal brain, we identified consistent dysregulation of axonal genes as an early risk factor for SCZ, providing novel insights into the effects of genetic predisposition on the neurodevelopmental origins of the disorder.Copyright © 2023. Published by Elsevier Inc.