Abstract
BackgroundProper 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.ResultsHere 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0165-3) contains supplementary material, which is available to authorized users.
Highlights
Proper neuronal function requires tight control of gene dosage, and failure of this process underlies the pathogenesis of multiple neuropsychiatric disorders
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
By investigating the relationship between the miRNAs and dosage-sensitive genes associated with the same type of neuropsychiatric disorder, we might gain some insight, not just into the pathogenesis of the disorder, and into the miRNAmediated regulation of dosage-sensitive genes. We examine this possibility for the SHANK3 gene and report post-transcriptional regulation of SHANK3 expression by three miRNAs, miR-7, miR34a, and miR-504, which were previously shown to be altered in some neuropsychiatric disorders that could be caused by SHANK3 dosage changes
Summary
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. The regulatory mechanism of SHANK3 expression in neurons itself is poorly understood Accumulating evidence from both human and animal model studies suggests that genetic variants are critical risk factors for various neuropsychiatric disorders [1]. 22q13.3, both deletions and duplications in which are associated with neuropsychiatric disorders [2,3,4] This suggests that the correct dosage of some genes within these loci is critical for normal brain function, and that there should be some regulatory mechanism in the brain to tightly control the expression of these dosage-sensitive genes.
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