title: MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex.
abstract: Loss- and gain-of-function mutations of the X-linked gene MECP2 (methyl-CpG binding protein 2) lead to severe neurodevelopmental disorders in humans, such as Rett syndrome (RTT) and autism. MeCP2 is previously known as a transcriptional repressor by binding to methylated DNA and recruiting histone deacetylase complex (HDAC). Here, we report that MeCP2 regulates gene expression posttranscriptionally by suppressing nuclear microRNA processing. We found that MeCP2 binds directly to DiGeorge syndrome critical region 8 (DGCR8), a critical component of the nuclear microRNA-processing machinery, and interferes with the assembly of Drosha and DGCR8 complex. Protein targets of MeCP2-suppressed microRNAs include CREB, LIMK1, and Pumilio2, which play critical roles in neural development. Gain of function of MeCP2 strongly inhibits dendritic and spine growth, which depends on the interaction of MeCP2 and DGCR8. Thus, control of microRNA processing via direct interaction with DGCR8 represents a mechanism for MeCP2 regulation of gene expression and neural development.
authors.affiliation: Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Tian-Lin
authors.initials: TL
authors.lastname: Cheng
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.
authors.forename: Zhizhi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Qiuming
authors.initials: Q
authors.lastname: Liao
authors.affiliation: Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Neonatology, Children's Hospital, Fudan University, Shanghai 201102, China.
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Zhou
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Xu
authors.affiliation: Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: zqiu@ion.ac.cn.
authors.forename: Zilong
authors.initials: Z
authors.lastname: Qiu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000235:genetics*; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry / Q000235:genetics; D049229:Dendritic Spines / Q000502:physiology*; D059014:High-Throughput Nucleotide Sequencing; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D047468:Immunoprecipitation; D051783:Methyl-CpG-Binding Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C474044:Dgcr8 protein, mouse; C497393:Mecp2 protein, mouse; C497394:Mecp2 protein, rat; D051783:Methyl-CpG-Binding Protein 2; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C513400:Drosha protein, mouse; D043244:Ribonuclease III