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Post-transcriptional regulation of SHANK3 expression by microRNAs related to multiple neuropsychiatric disorders.

Molecular brain | Nov 16, 2015

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.

Pubmed ID: 26572867 RIS Download

Mesh terms: 3' Untranslated Regions | Animals | Base Sequence | Cells, Cultured | Dendritic Spines | HEK293 Cells | Hippocampus | Humans | Lentivirus | Luciferases | Male | Mental Disorders | Mice, Inbred C57BL | MicroRNAs | Molecular Sequence Data | Nerve Tissue Proteins | Protein Interaction Mapping | Reproducibility of Results | Transcription, Genetic

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BrainSpan: Atlas of the Developing Human Brain

An atlas of the developing human brain designed as a foundational resource for studying transcriptional mechanisms involved in human brain development. The atlas consists of a variety of data modalities and data mining tools. It contains RNA sequencing and exon microarray data profiling up to sixteen cortical and subcortical structures across the full course of human brain development, as well as high-resolution neuroanatomical transcriptional profiles of about 300 distinct structures spanning the entire brain for four midgestional prenatal specimens. Also included are a high-resolution in situ hybridization image data covering selected genes and brain regions in developing and adult human brain, and a reference atlas in full color with high-resolution anatomic reference atlases of prenatal (two stages) and adult human brain along with supporting histology, magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) data.

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miRDB

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NeuroMab

A national mouse monoclonal antibody generating resource for biochemical and immunohistochemical applications in mammalian brain. NeuroMabs are generated from mice immunized with synthetic and recombinant immunogens corresponding to components of the neuronal proteome as predicted from genomic and other large-scale cloning efforts. Comprehensive biochemical and immunohistochemical analyses of human, primate and non-primate mammalian brain are incorporated into the initial NeuroMab screening procedure. This yields a subset of mouse mAbs that are optimized for use in brain (i.e. NeuroMabs): for immunocytochemical-based imaging studies of protein localization in adult, developing and pathological brain samples, for biochemical analyses of subunit composition and post-translational modifications of native brain proteins, and for proteomic analyses of native brain protein networks. The NeuroMab facility was initially funded with a five-year U24 cooperative grant from NINDS and NIMH. The initial goal of the facility for this funding period is to generate a library of novel NeuroMabs against neuronal proteins, initially focusing on membrane proteins (receptors/channels/transporters), synaptic proteins, other neuronal signaling molecules, and proteins with established links to disease states. The scope of the facility was expanded with supplements from the NIH Blueprint for Neuroscience Research to include neurodevelopmental targets, the NIH Roadmap for Medical Research to include epigenetics targets, and NIH Office of Rare Diseases Research to include rare disease targets. These NeuroMabs will then be produced on a large scale and made available to the neuroscience research community on an inexpensive basis as tissue culture supernatants or purified immunoglobulin by Antibodies Inc. The UC Davis/NIH NeuroMab Facility makes NeuroMabs available directly to end users and is unable to accommodate sales to distributors for third party distribution. Note, NeuroMab antibodies are now offered through antibodiesinc.

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