@article{8b1bb6b8284c4f26b76239ba81b51ae9,
title = "A human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies",
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.",
author = "Yunhee Kang and Ying Zhou and Yujing Li and Yanfei Han and Jie Xu and Weibo Niu and Ziyi Li and Shiying Liu and Hao Feng and Wen Huang and Ranhui Duan and Tianmin Xu and Nisha Raj and Feiran Zhang and Juan Dou and Chongchong Xu and Hao Wu and Bassell, {Gary J.} and Warren, {Stephen T.} and Allen, {Emily G.} and Peng Jin and Zhexing Wen",
note = "Funding Information: This work is dedicated to the late S. Warren and was supported, in part, by the National Institutes of Health (NS091859 to S.T.W. and P.J.; HD104458 to S.T.W., P.J., G.B. and Z.W.; HD082013 to G.B.; AI131130 to Z.W. and P.J.; MH123711 and MH121102 to Z.W.; and NS051630 and NS111602 to P.J.), the Department of Defense (W81XWH1910068 to E.G.A. and W81XWH1910353 to Z.W.), the Edward Mallinckrodt, Jr. Foundation (Z.W.) and the FRAXA Research Foundation (Y.K.). We would like to thank S. Sloan at Emory University for help with scRNA-seq analyses. This study was supported, in part, by the Emory Integrated Genomics Core, which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. This work was performed with the support of the Georgia Genomics and Bioinformatics Core (GGBC) at the University of Georgia. The scRNA-seq work was performed at the GGBC at the University of Georgia, Athens. We thank M. Alabady and his team at the GGBC for their support and contribution to this work. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = oct,
doi = "10.1038/s41593-021-00913-6",
language = "English (US)",
volume = "24",
pages = "1377--1391",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "10",
}