Open AccessA human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies
Author(s) -
Yunhee Kang,
Ying Zhou,
Yujing Li,
Yanfei Han,
Jie Xu,
Weibo Niu,
Ziyi Li,
Shiying Liu,
Hao Feng,
Wen Huang,
Ranhui Duan,
Tingting Xu,
Nisha Raj,
Feiran Zhang,
Jingtao Dou,
Chi Xu,
Hao Wu,
Gary J. Bassell,
Stephen T. Warren,
Emily G. Allen,
Peng Jin,
Zhexing Wen
Publication year - 2021
Publication title -
nature neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 13.403
H-Index - 422
eISSN - 1546-1726
pISSN - 1097-6256
DOI - 10.1038/s41593-021-00913-6
Subject(s) - forebrain , fragile x syndrome , biology , neurogenesis , neuroscience , organoid , human brain , microbiology and biotechnology , genetics , central nervous system
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.