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

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

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1377-1391
Number of pages15
JournalNature Neuroscience
Volume24
Issue number10
DOIs
StatePublished - Oct 2021

ASJC Scopus subject areas

  • General Neuroscience

MD Anderson CCSG core facilities

  • Biostatistics Resource Group

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