Stem Cell Research Lab, Racine IVF Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, 6 Weizmann St., 64239 Tel-Aviv, Israel.
Dev Biol. 2013 Feb 1;374(1):32-45. doi: 10.1016/j.ydbio.2012.11.031. Epub 2012 Dec 5.
Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability, caused by developmentally regulated inactivation of FMR1, leading to the absence of its encoded protein FMRP. We have previously shown that undifferentiated Fragile X human Embryonic Stem Cells (FX-hESCs) express FMRP, despite the presence of the full FMR1 mutation (>200 CGG repeats). We describe here, for the first time, in-vitro differentiation of FX-hESCs into neurons progressively inactivating FMR1. Abnormal neurogenesis and aberrant gene expression were found already during early stages of differentiation, leading to poor neuronal maturation and high gliogenic development. Human FX neurons fired action potentials but displayed poor spontaneous synaptic activity and lacked reactivity to glutamate. Our dynamic FX-hESCs model can contribute to the understanding of the sequence of developmental events taking place during neurogenesis and how they are altered in FXS individuals, leading to intellectual disability. Furthermore, it may shed light over the striking phenotypic features characterizing FXS in human.
脆性 X 综合征（FXS）是最常见的遗传性智力障碍，由 FMR1 的发育调控失活引起，导致其编码的蛋白 FMRP 缺失。我们之前已经表明，未分化的脆性 X 人类胚胎干细胞（FX-hESC）尽管存在完整的 FMR1 突变（>200 CGG 重复），但仍表达 FMRP。我们在这里首次描述了 FX-hESC 在体外逐渐分化为神经元，从而逐渐失活 FMR1。在分化的早期阶段就发现了异常的神经发生和异常的基因表达，导致神经元成熟不良和高神经胶质发育。人类 FX 神经元可以产生动作电位，但自发突触活动较差，对谷氨酸无反应。我们的动态 FX-hESC 模型有助于理解神经发生过程中发生的发育事件的顺序，以及它们在 FXS 个体中是如何改变的，从而导致智力障碍。此外，它可能阐明了 FXS 在人类中表现出的显著表型特征。
