小柯机器人

美国埃默里大学医学院Zhexing Wen和Peng Jin研究组合作取得最新进展。脆性 X 综合征 (FXS)的人类前脑类器官模型表现出改变的神经发生并强调了新的治疗策略。这一研究成果发表在2021年8月19日出版的国际学术期刊《自然—神经科学》上。

在这项研究中，他们开发了 FXS 人类前脑类器官模型，并观察到脆性 X 智力低下蛋白 (FMRP)的丧失导致神经发生、神经元成熟和神经元兴奋性失调。FXS 前脑类器官的整体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磷酸肌醇 3-激酶途径而不是 FXS 小鼠模型中破坏的代谢型谷氨酸途径来挽救。

他们鉴定了大量由 FMRP 结合的人类特异性 mRNA。这些人类特异性 FMRP 靶标之一 CHD2 导致 FXS 类器官中基因表达的改变。总的来说，他们的研究揭示了与人类大脑发育过程中 FMRP 损失相关的分子、细胞和电生理异常。

据介绍，FXS 是由FMRP丢失引起的，FMRP 是一种可以调节特定 mRNA 翻译的 RNA 结合蛋白。

附：英文原文

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

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

Issue&Volume: 2021-08-19

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. 

DOI: 10.1038/s41593-021-00913-6

Source: https://www.nature.com/articles/s41593-021-00913-6

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex