Neuronal Histone Methyltransferase EZH2 Regulates Neuronal Morphogenesis,Synaptic Plasticity,and Cognitive Behavior in Mice

Mei Zhang ¹Yong Zhang ²Qian Xu ²Joshua Crawford ³Cheng Qian ⁴Guo-Hua Wang ⁵Jiang Qian ⁵Xin-Zhong Dong ²Mikhail V.Pletnikov ³Chang-Mei Liu ⁶Feng-Quan Zhou⁷

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作者信息

1. Department of Orthopaedic Surgery,Johns Hopkins University School of Medicine,Baltimore 21205,USA;School of Life Sciences,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei 230026,China
2. The Solomon H.Snyder Department of Neuroscience,Johns Hopkins University School of Medicine,Baltimore 21205,USA
3. Department of Psychiatry and Behavioral Sciences,Johns Hopkins University School of Medicine,Baltimore 21205,USA
4. Department of Orthopaedic Surgery,Johns Hopkins University School of Medicine,Baltimore 21205,USA
5. Department of Ophthalmology,Johns Hopkins University School of Medicine,Baltimore 21205,USA
6. Department of Orthopaedic Surgery,Johns Hopkins University School of Medicine,Baltimore 21205,USA;State Key Laboratory of Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100190,China
7. Department of Orthopaedic Surgery,Johns Hopkins University School of Medicine,Baltimore 21205,USA;The Solomon H.Snyder Department of Neuroscience,Johns Hopkins University School of Medicine,Baltimore 21205,USA;Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou 310016,China
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Abstract

The histone methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit(EZH2)-medi-ated trimethylation of histone H3 lysine 27(H3K27me3)regulates neural stem cell proliferation and fate specificity through silencing different gene sets in the central nervous system.Here,we explored the function of EZH2 in early post-mitotic neurons by generating a neuron-specific Ezh2 conditional knockout mouse line.The results showed that a lack of neuronal EZH2 led to delayed neuronal migration,more complex dendritic arborization,and increased den-dritic spine density.Transcriptome analysis revealed that neuronal EZH2-regulated genes are related to neuronal mor-phogenesis.In particular,the gene encoding p21-activated kinase 3(Pak3)was identified as a target gene suppressed by EZH2 and H3K27me3,and expression of the dominant neg-ative Pak3 reversed Ezh2 knockout-induced higher dendritic spine density.Finally,the lack of neuronal EZH2 resulted in impaired memory behaviors in adult mice.Our results demonstrated that neuronal EZH2 acts to control multiple steps of neuronal morphogenesis during development,and has long-lasting effects on cognitive function in adult mice.

Key words

Neural development/Dendritic branching/Dendritic spine/Cognitive function/Epigenetics/Histone methylation/EZH2

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基金项目

NIH(R01NS064288)

NIH(R01NS085176)

NIH(R01GM111514)

NIH(R01EY027347)

Craig H.Neilsen Foundation(259450)

BrightFocus Foundation(G2017037)

出版年

2023

神经科学通报(英文版)

中国科学院上海生命科学研究院

神经科学通报(英文版)

CSTPCDCSCD

影响因子：0.741

ISSN：1673-7067

参考文献量53

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