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. Here we have developed an FXS human forebrain organoid model and observed 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.