Thalamic dysfunction has been implicated in multiple psychiatric disorders. We sought to study the mechanisms by which abnormalities emerge in the context of the 22q11.2 microdeletion, which confers significant genetic risk for psychiatric disorders. We investigated early stages of human thalamus development using human pluripotent stem cell-derived organoids and show that the 22q11.2 microdeletion underlies widespread transcriptional dysregulation associated with psychiatric disorders in thalamic neurons and glia, including elevated expression of . Using an organoid co-culture model, we demonstrate that the 22q11.2 microdeletion mediates an overgrowth of thalamic axons in a FOXP2-dependent manner. Finally, we identify ROBO2 as a candidate molecular mediator of the effects of FOXP2 overexpression on thalamic axon overgrowth. Together, our study suggests that early steps in thalamic development are dysregulated in a model of genetic risk for schizophrenia and contribute to neural phenotypes in 22q11.2 deletion syndrome.

中文翻译：

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丘脑皮质类器官能够对与神经精神疾病相关的 22q11.2 微缺失进行体外建模

丘脑功能障碍与多种精神疾病有关。我们试图研究 22q11.2 微缺失背景下出现异常的机制，该微缺失给精神疾病带来了显着的遗传风险。我们使用人类多能干细胞衍生的类器官研究了人类丘脑发育的早期阶段，并表明 22q11.2 微缺失是与丘脑神经元和神经胶质细胞精神疾病相关的广泛转录失调的基础，包括 . 使用类器官共培养模型，我们证明 22q11.2 微缺失以 FOXP2 依赖性方式介导丘脑轴突的过度生长。最后，我们将 ROBO2 确定为 FOXP2 过表达对丘脑轴突过度生长影响的候选分子介导物。总之，我们的研究表明，在精神分裂症遗传风险模型中，丘脑发育的早期步骤失调，并导致 22q11.2 缺失综合征的神经表型。