Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation
Summary: 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 s...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-04-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720304204 |
| id |
doaj-a4429567bc564f6c9b55521ae9a3cf26 |
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| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Ke Zhang Fang Yu Jian Zhu Sue Han Jiehui Chen Xuanyuan Wu Yingying Chen Tingyu Shen Jiaoyang Liao Wenke Guo Xianfa Yang Ran Wang Yun Qian Jiaxin Yang Leping Cheng Yun Zhao Chi-Chung Hui Jinsong Li Guangdun Peng Shuijin He Naihe Jing Ke Tang |
| spellingShingle |
Ke Zhang Fang Yu Jian Zhu Sue Han Jiehui Chen Xuanyuan Wu Yingying Chen Tingyu Shen Jiaoyang Liao Wenke Guo Xianfa Yang Ran Wang Yun Qian Jiaxin Yang Leping Cheng Yun Zhao Chi-Chung Hui Jinsong Li Guangdun Peng Shuijin He Naihe Jing Ke Tang Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation Cell Reports |
| author_facet |
Ke Zhang Fang Yu Jian Zhu Sue Han Jiehui Chen Xuanyuan Wu Yingying Chen Tingyu Shen Jiaoyang Liao Wenke Guo Xianfa Yang Ran Wang Yun Qian Jiaxin Yang Leping Cheng Yun Zhao Chi-Chung Hui Jinsong Li Guangdun Peng Shuijin He Naihe Jing Ke Tang |
| author_sort |
Ke Zhang |
| title |
Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation |
| title_short |
Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation |
| title_full |
Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation |
| title_fullStr |
Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation |
| title_full_unstemmed |
Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation |
| title_sort |
imbalance of excitatory/inhibitory neuron differentiation in neurodevelopmental disorders with an nr2f1 point mutation |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2020-04-01 |
| description |
Summary: 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 corresponding Nr2f1 point-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. : Zhang et al. find that a NR2F1-R112K mutation promotes inhibitory neuron differentiation by activating the Hedgehog signaling pathway, and corresponding mutant mice display behavioral deficits related to neurodevelopmental disorders, including autistic spectrum disorder (ASD), which could be partially alleviated by antagonizing the inhibitory synaptic transmission. Keywords: neurodevelopmental disorders, autism spectrum disorders, excitatory neuron, inhibitory neuron, dorsal neuron progenitor cell, ventral neuron progenitor cell, E/I imbalance, Hedgehog signaling pathway, NR2F1 |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124720304204 |
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doaj-a4429567bc564f6c9b55521ae9a3cf262020-11-25T02:41:40ZengElsevierCell Reports2211-12472020-04-01313Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point MutationKe Zhang0Fang Yu1Jian Zhu2Sue Han3Jiehui Chen4Xuanyuan Wu5Yingying Chen6Tingyu Shen7Jiaoyang Liao8Wenke Guo9Xianfa Yang10Ran Wang11Yun Qian12Jiaxin Yang13Leping Cheng14Yun Zhao15Chi-Chung Hui16Jinsong Li17Guangdun Peng18Shuijin He19Naihe Jing20Ke Tang21State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, ChinaState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, ChinaPrecise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, Guangdong 510006, ChinaState Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, ChinaState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, ChinaState Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, ChinaState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, ChinaState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, ChinaState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, ChinaState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, ChinaState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, ChinaPrecise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, Guangdong 510006, ChinaState Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Collaborative Innovation Center for Biomedicine and Guangxi Key Laboratory of Regenerative Medicine, School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, ChinaState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, ChinaProgram in Developmental & Stem Cell Biology, Research Institute, Hospital for Sick Children, Toronto, ON M5G 0A4, CanadaState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, ChinaCAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China; Center for Cell Lineage and Atlas, Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou, Guangdong 510005, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Corresponding authorState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China; Center for Cell Lineage and Atlas, Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou, Guangdong 510005, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Corresponding authorPrecise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, Guangdong 510006, China; Corresponding authorSummary: 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 corresponding Nr2f1 point-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. : Zhang et al. find that a NR2F1-R112K mutation promotes inhibitory neuron differentiation by activating the Hedgehog signaling pathway, and corresponding mutant mice display behavioral deficits related to neurodevelopmental disorders, including autistic spectrum disorder (ASD), which could be partially alleviated by antagonizing the inhibitory synaptic transmission. Keywords: neurodevelopmental disorders, autism spectrum disorders, excitatory neuron, inhibitory neuron, dorsal neuron progenitor cell, ventral neuron progenitor cell, E/I imbalance, Hedgehog signaling pathway, NR2F1http://www.sciencedirect.com/science/article/pii/S2211124720304204 |