Journal Article

A human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies

Wu, Hao, Xu, Tianmin, Duan, Ranhui, Xu, Chongchong, Wen, Zhexing, Zhou, Ying, Kang, Yunhee, Liu, Shiying, Xu, Jie, Huang, Wen, Dou, Juan, Feng, Hao, Allen, Emily G., Niu, Weibo, Raj, Nisha, Li, Yujing, Bassell, Gary J., Li, Ziyi, Zhang, Feiran, Jin, Peng, Han, Yanfei, Warren, Stephen T.

2021

Overview

Fragile X syndrome (FXS) is caused by the loss of fragile X mental retardation protein (FMRP), an RNA-binding protein that can regulate the translation of specific mRNAs. In this study, we developed an FXS human forebrain organoid model and observed that the loss of FMRP led to dysregulated neurogenesis, neuronal maturation and neuronal excitability. Bulk and single-cell gene expression analyses of FXS forebrain organoids revealed that the loss of FMRP altered gene expression in a cell-type-specific manner. The developmental deficits in FXS forebrain organoids could be rescued by inhibiting the phosphoinositide 3-kinase pathway but not the metabotropic glutamate pathway disrupted in the FXS mouse model. We identified a large number of human-specific mRNAs bound by FMRP. One of these human-specific FMRP targets, CHD2, contributed to the altered gene expression in FXS organoids. Collectively, our study revealed molecular, cellular and electrophysiological abnormalities associated with the loss of FMRP during human brain development. Using a human forebrain organoid model of fragile X syndrome, Kang et al. reveal a critical role of FMRP in human brain development and identify a large number of human-specific mRNAs that could be regulated by FMRP.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/100 / 45/44 / 631/208/366/1373 / 631/337/1645 / 631/378/1689/2608 / 631/378/2571/2579 / 631/532/2182 / 82/51 / 96/106 / Abnormalities / Adult / Animal Genetics and Genomics / Behavioral Sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Brain / Brain - pathology / Care and treatment / Cell Differentiation / Development and progression / Diagnosis / DNA-Binding Proteins - genetics / Electrophysiological Phenomena / Excitability / FMR1 protein / Forebrain / Fragile X syndrome / Fragile X Syndrome - drug therapy / Fragile X Syndrome - pathology / Gene expression / Glutamic acid receptors (metabotropic) / Humans / Intellectual disabilities / Kinases / Male / Models, Neurological / Neurobiology / Neurogenesis / Neurogenesis - drug effects / Neurogenesis - genetics / Neurons - pathology / Neurosciences / Organoids / Phosphatidylinositol 3-Kinases - drug effects / Prosencephalon / Prosencephalon - pathology / Protein Binding / Protein Kinase Inhibitors - therapeutic use / Proteins / Receptors, Metabotropic Glutamate - drug effects / RNA, Messenger - genetics / RNA-binding protein