Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation.

Animals Autism Spectrum Disorder / genetics COUP Transcription Factor I / genetics Cell Differentiation / physiology Hedgehog Proteins / metabolism Humans Mice Neurodevelopmental Disorders / genetics Neurons / metabolism Point Mutation Signal Transduction
E/I imbalance Hedgehog signaling pathway NR2F1 autism spectrum disorders dorsal neuron progenitor cell excitatory neuron inhibitory neuron neurodevelopmental disorders ventral neuron progenitor cell

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
21 04 2020
Historique:
received: 12 08 2019
revised: 13 12 2019
accepted: 24 03 2020
entrez: 23 4 2020
pubmed: 23 4 2020
medline: 15 5 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.celrep.2020.03.085 PMID: 32320667
pubmed: 32320667
pii: S2211-1247(20)30420-4
doi: 10.1016/j.celrep.2020.03.085
pii:
doi:

Substances chimiques

COUP Transcription Factor I 0
Hedgehog Proteins 0
NR2F1 protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

107521

Informations de copyright

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.

Auteurs

Ke Zhang (K)

State 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.

Fang Yu (F)

State 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.

Jian Zhu (J)

Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, Guangdong 510006, China.

Sue Han (S)

State 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.

Jiehui Chen (J)

State 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.

Xuanyuan Wu (X)

School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.

Yingying Chen (Y)

State 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.

Tingyu Shen (T)

State 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.

Jiaoyang Liao (J)

State 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.

Wenke Guo (W)

State 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.

Xianfa Yang (X)

State 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, China.

Ran Wang (R)

State 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.

Yun Qian (Y)

State 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.

Jiaxin Yang (J)

Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, Guangdong 510006, China.

Leping Cheng (L)

State 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, China.

Yun Zhao (Y)

State 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.

Chi-Chung Hui (CC)

Program in Developmental & Stem Cell Biology, Research Institute, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.

Jinsong Li (J)

State 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.

Guangdun Peng (G)

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.

Shuijin He (S)

School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: heshj@shanghaitech.edu.cn.

Naihe Jing (N)

State 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. Electronic address: njing@sibcb.ac.cn.

Ke Tang (K)

Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, Guangdong 510006, China. Electronic address: tangke@gzhu.edu.cn.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Imbalance of Excitatory/Inhibitory Neuron...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Troubles généralisés du développement de l'enfant › Trouble du spectre autistique › Imbalance of Excitatory/Inhibitory Neuron...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Facteur de transcription COUP-TFI › Imbalance of Excitatory/Inhibitory Neuron...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Différenciation cellulaire › Imbalance of Excitatory/Inhibitory Neuron...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines Hedgehog › Imbalance of Excitatory/Inhibitory Neuron...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Imbalance of Excitatory/Inhibitory Neuron...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Imbalance of Excitatory/Inhibitory Neuron...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Imbalance of Excitatory/Inhibitory Neuron...
questionsmedicales.fr › Cellules › Neurones › Imbalance of Excitatory/Inhibitory Neuron...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation ponctuelle › Imbalance of Excitatory/Inhibitory Neuron...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Imbalance of Excitatory/Inhibitory Neuron...