Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation
Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation
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NR2F1 点突变神经发育障碍中兴奋性/抑制性神经元分化的不平衡
DOI：
10.1016/j.celrep.2020.03.085
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发表时间：
2020
期刊：
影响因子：
8.8
通讯作者：
Tang Ke
中科院分区：
文献类型：
--
作者：
Zhang Ke;Yu Fang;Zhu Jian;Han Sue;Chen Jiehui;Wu Xuanyuan;Chen Yingying;Shen Tingyu;Liao Jiaoyang;Guo Wenke;Yang Xianfa;Wang Ran;Qian Yun;Yang Jiaxin;Cheng Leping;Zhao Yun;Hui Chi-Chung;Li Jinsong;Peng Guangdun;He Shuijin;Jing Naihe;Tang Ke
最近的研究揭示了胚胎皮层发育在神经发育障碍，包括自闭症谱系障碍（ASD）的病理生理学中的重要作用。然而，遗传基础和潜在机制仍不清楚。在这里，我们产生突变的人胚胎干细胞系（Mut hESC）携带NR 2F 1-R112 K突变，已确定在ASD患者的功能和调查他们的神经发育改变。Mut hESC过度产生腹侧端脑神经元祖细胞（腹侧NPC）而产生不足的背侧NPC，导致兴奋性/抑制性神经元的不平衡。这些改变主要归因于异常激活的Hedgehog信号通路。此外，相应的Nr 2f 1点突变小鼠表现出类似的兴奋/抑制神经元失衡和异常行为。拮抗增加的抑制性突触传递部分减轻了他们的行为缺陷。总之，我们的研究结果表明，NR 2F 1依赖的兴奋性/抑制性神经元分化的激活刺猬通路所造成的不平衡是神经发育障碍的前兆之一，并可能启发治疗方法。
Recent studies have revealed an essential role for embryonic cortical development in the pathophysiology of neurodevelopmental disorders, including autism spectrum disorder (ASD). However, the genetic basis and underlying mechanisms remain unclear. Here, we generate mutant human embryonic stem cell lines (Mut hESCs) carrying an NR2F1-R112K mutation that has been identified in a patient with ASD features and investigate their neurodevelopmental alterations. Mut hESCs overproduce ventral telencephalic neuron progenitors (ventral NPCs) and underproduce dorsal NPCs, causing the imbalance of excitatory/inhibitory neurons. These alterations can be mainly attributed to the aberrantly activated Hedgehog signaling pathway. Moreover, the correspondingNr2f1point-mutant mice display a similar excitatory/inhibitory neuron imbalance and abnormal behaviors. Antagonizing the increased inhibitory synaptic transmission partially alleviates their behavioral deficits. Together, our results suggest that the NR2F1-dependent imbalance of excitatory/inhibitory neuron differentiation caused by the activated Hedgehog pathway is one precursor of neurodevelopmental disorders and may enlighten the therapeutic approaches.