title: Post-transcriptional regulation of SHANK3 expression by microRNAs related to multiple neuropsychiatric disorders.
abstract: BACKGROUND
  Proper neuronal function requires tight control of gene dosage, and failure of this process underlies the pathogenesis of multiple neuropsychiatric disorders. The SHANK3 gene encoding core scaffolding proteins at glutamatergic postsynapse is a typical dosage-sensitive gene, both deletions and duplications of which are associated with Phelan-McDermid syndrome, autism spectrum disorders, bipolar disorder, intellectual disability, or schizophrenia. However, the regulatory mechanism of SHANK3 expression in neurons itself is poorly understood.
  
  
  RESULTS
  Here we show post-transcriptional regulation of SHANK3 expression by three microRNAs (miRNAs), miR-7, miR-34a, and miR-504. Notably, the expression profiles of these miRNAs were previously shown to be altered in some neuropsychiatric disorders which are also associated with SHANK3 dosage changes. These miRNAs regulated the expression of SHANK3 and other genes encoding actin-related proteins that interact with Shank3, through direct binding sites in the 3' untranslated region (UTR). Moreover, overexpression or inhibition of miR-7 and miR-504 affected the dendritic spines of the cultured hippocampal neurons in a Shank3-dependent manner. We further characterized miR-504 as it showed the most significant effect on both SHANK3 expression and dendritic spines among the three miRNAs. Lentivirus-mediated overexpression of miR-504, which mimics its reported expression change in postmortem brain tissues of bipolar disorder, decreased endogenous Shank3 protein in cultured hippocampal neurons. We also revealed that miR-504 is expressed in the cortical and hippocampal regions of human and mouse brains.
  
  
  CONCLUSIONS
  Our study provides new insight into the miRNA-mediated regulation of SHANK3 expression, and its potential implication in multiple neuropsychiatric disorders associated with altered SHANK3 and miRNA expression profiles.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, South Korea. sychoi0307@gmail.com.|Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, 305-701, South Korea. sychoi0307@gmail.com.
authors.forename: Su-Yeon
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, 77030, USA. kpang@bcm.edu.|Department of Pediatrics, Baylor College of Medicine, Computational and Integrative Biomedical Research Center, Houston, 77030, USA. kpang@bcm.edu.
authors.forename: Kaifang
authors.initials: K
authors.lastname: Pang
authors.affiliation: Department of Anatomy and Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Seoul, 136-705, South Korea. eleneu@korea.ac.kr.
authors.forename: Joo Yeon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Seoul, 136-705, South Korea. jaeryunryu@korea.ac.kr.
authors.forename: Jae Ryun
authors.initials: JR
authors.lastname: Ryu
authors.affiliation: HPC-enabled Convergence Technology Research Division, Korea Institute of Science and Technology Information, Daejeon, 305-701, South Korea. hjkang.kr@gmail.com.
authors.forename: Hyojin
authors.initials: H
authors.lastname: Kang
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, 77030, USA. zhandonl@bcm.edu.|Department of Pediatrics, Baylor College of Medicine, Computational and Integrative Biomedical Research Center, Houston, 77030, USA. zhandonl@bcm.edu.
authors.forename: Zhandong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Neuroscience and Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Seoul, 136-705, South Korea. wonki@korea.ac.kr.
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Seoul, 136-705, South Korea. woongsun@korea.ac.kr.
authors.forename: Woong
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Anatomy and Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Seoul, 136-705, South Korea. kimhyun@korea.ac.kr.|Department of Neuroscience and Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Seoul, 136-705, South Korea. kimhyun@korea.ac.kr.
authors.forename: Hyun
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Neuroscience and Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Seoul, 136-705, South Korea. neurohan@korea.ac.kr.
authors.forename: Kihoon
authors.initials: K
authors.lastname: Han
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D025941:Protein Interaction Mapping; D015203:Reproducibility of Results; D014158:Transcription, Genetic
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C492357:SHANK3 protein, human; C492356:Shank3 protein, mouse; D008156:Luciferases