小柯机器人

美国加州大学Tomasz J. Nowakowski团队近期取得重要工作进展，他们研究利用丘脑皮质类器官对与神经精神疾病相关的22q11.2微缺失进行体外建模。相关研究成果2024年2月20日在线发表于《细胞—干细胞》杂志上。

据介绍，丘脑功能障碍与多种精神疾病有关。

研究人员试图研究在22q11.2微缺失的背景下出现异常的机制，这会给精神疾病带来重大的遗传风险。研究人员使用人类多能干细胞来源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中的精神疾病相关的广泛转录失调的基础，包括FOXP2的表达升高。使用类器官共培养模型，研究人员证明22q11.2微缺失以FOXP2依赖的方式介导丘脑轴突的过度生长。最后，研究人员确定ROBO2是FOXP2过表达对丘脑轴突过度生长影响的候选分子介质。

总之，这一研究表明，在精神分裂症遗传风险模型中，丘脑发育的早期阶段是失调的，并导致22q11.2缺失综合征的神经表型。

附：英文原文

Title: Thalamocortical organoids enable in vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders

Author: David Shin, Chang N. Kim, Jayden Ross, Kelsey M. Hennick, Sih-Rong Wu, Neha Paranjape, Rachel Leonard, Jerrick C. Wang, Matthew G. Keefe, Bryan J. Pavlovic, Kevin C. Donohue, Clara Moreau, Emilie M. Wigdor, H. Hanh Larson, Denise E. Allen, Cathryn R. Cadwell, Aparna Bhaduri, Galina Popova, Carrie E. Bearden, Alex A. Pollen, Sebastien Jacquemont, Stephan J. Sanders, David Haussler, Arun P. Wiita, Nicholas A. Frost, Vikaas S. Sohal, Tomasz J. Nowakowski

Issue&Volume: 2024-02-20

Abstract: Thalamic dysfunction has been implicated in multiple psychiatric disorders. We soughtto study the mechanisms by which abnormalities emerge in the context of the 22q11.2microdeletion, which confers significant genetic risk for psychiatric disorders. Weinvestigated early stages of human thalamus development using human pluripotent stemcell-derived organoids and show that the 22q11.2 microdeletion underlies widespreadtranscriptional dysregulation associated with psychiatric disorders in thalamic neuronsand glia, including elevated expression of FOXP2. Using an organoid co-culture model, we demonstrate that the 22q11.2 microdeletionmediates an overgrowth of thalamic axons in a FOXP2-dependent manner. Finally, weidentify ROBO2 as a candidate molecular mediator of the effects of FOXP2 overexpressionon thalamic axon overgrowth. Together, our study suggests that early steps in thalamicdevelopment are dysregulated in a model of genetic risk for schizophrenia and contributeto neural phenotypes in 22q11.2 deletion syndrome.

DOI: 10.1016/j.stem.2024.01.010

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00040-7

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