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.

脆性 X 综合征 (FXS) 是由脆性 X 智力迟钝蛋白 (FMRP) 的缺失引起的，FMRP 是一种可调节特定 mRNA 翻译的 RNA 结合蛋白。在这项研究中，我们开发了一个 FXS 人类前脑类器官模型，并观察到 ​​FMRP 的缺失导致神经发生、神经元成熟和神经元兴奋性失调。FXS 前脑类器官的大量和单细胞基因表达分析表明，FMRP 的缺失以细胞类型特异性方式改变了基因表达。FXS 前脑类器官的发育缺陷可以通过抑制 FXS 小鼠模型中破坏的磷酸肌醇 3-激酶途径而不是代谢型谷氨酸途径来挽救。我们确定了大量由 FMRP 结合的人类特异性 mRNA。这些人类特异性 FMRP 目标之一，CHD2，促成了 FXS 类器官中基因表达的改变。总的来说，我们的研究揭示了与人类大脑发育过程中 FMRP 丧失相关的分子、细胞和电生理异常。