Zhao Xingsen, Sun Qihang, Shou Yikai, Chen Weijun, Wang Mengxuan, Qu Wenzheng, Huang Xiaoli, Li Ying, Wang Chao, Gu Yan, Ji Chai, Shu Qiang, Li Xuekun
The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang University, Hangzhou, China.
The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China.
Elife. 2024 Dec 13;13:RP98081. doi: 10.7554/eLife.98081.
Williams syndrome (WS; OMIM#194050) is a rare disorder, which is caused by the microdeletion of one copy of 25-27 genes, and WS patients display diverse neuronal deficits. Although remarkable progresses have been achieved, the mechanisms for these distinct deficits are still largely unknown. Here, we have shown that neural progenitor cells (NPCs) in WS forebrain organoids display abnormal proliferation and differentiation capabilities, and synapse formation. Genes with altered expression are related to neuronal development and neurogenesis. Single cell RNA-seq (scRNA-seq) data analysis revealed 13 clusters in healthy control and WS organoids. WS organoids show an aberrant generation of excitatory neurons. Mechanistically, the expression of transthyretin (TTR) are remarkably decreased in WS forebrain organoids. We have found that GTF2IRD1 encoded by one WS associated gene binds to promoter regions and regulates the expression of . In addition, exogenous TTR can activate ERK signaling and rescue neurogenic deficits of WS forebrain organoids. -deficient mice display similar neurodevelopmental deficits as observed in WS organoids. Collectively, our study reveals critical function of GTF2IRD1 in regulating neurodevelopment of WS forebrain organoids and mice through regulating TTR-ERK pathway.
威廉姆斯综合征（WS；OMIM#194050）是一种罕见疾病，由25 - 27个基因中的一个拷贝发生微缺失引起，WS患者表现出多种神经元缺陷。尽管已取得显著进展，但这些明显缺陷的机制仍大多未知。在此，我们表明WS前脑类器官中的神经祖细胞（NPCs）表现出异常的增殖、分化能力以及突触形成。表达改变的基因与神经元发育和神经发生有关。单细胞RNA测序（scRNA-seq）数据分析揭示了健康对照和WS类器官中的13个细胞簇。WS类器官显示出兴奋性神经元的异常生成。从机制上讲，转甲状腺素蛋白（TTR）在WS前脑类器官中的表达显著降低。我们发现一个与WS相关基因编码的GTF2IRD1与启动子区域结合并调节其表达。此外，外源性TTR可激活ERK信号并挽救WS前脑类器官的神经发生缺陷。 -缺陷小鼠表现出与WS类器官中观察到的类似神经发育缺陷。总体而言，我们的研究揭示了GTF2IRD1通过调节TTR - ERK途径在调节WS前脑类器官和小鼠神经发育中的关键作用。
