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Schizophrenia is associated with an increase in cortical microRNA biogenesis.

Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ - Mol. Psychiatry (2009)

Bottom Line: MicroRNA expression profiling and quantitative reverse transcription-PCR analysis of the superior temporal gyrus and the dorsolateral prefrontal cortex revealed a significant schizophrenia-associated increase in global microRNA expression.This change was associated with an elevation of primary microRNA processing and corresponded with an increase in the microprocessor component DGCR8.The biological implications for this extensive increase in gene silencing are profound, and were exemplified by members of the miR-15 family and other related microRNA, which were significantly upregulated in both brain regions.

View Article: PubMed Central - PubMed

Affiliation: Schizophrenia Research Institute, Sydney, NSW, Australia.

ABSTRACT
MicroRNA expression profiling and quantitative reverse transcription-PCR analysis of the superior temporal gyrus and the dorsolateral prefrontal cortex revealed a significant schizophrenia-associated increase in global microRNA expression. This change was associated with an elevation of primary microRNA processing and corresponded with an increase in the microprocessor component DGCR8. The biological implications for this extensive increase in gene silencing are profound, and were exemplified by members of the miR-15 family and other related microRNA, which were significantly upregulated in both brain regions. This functionally convergent influence is overrepresented in pathways involved in synaptic plasticity and includes many genes and pathways associated with schizophrenia, some of which were substantiated in vitro by reporter gene assay. Given the magnitude of microRNA changes and their wide sphere of influence, this phenomenon could represent an important dimension in the pathogenesis of schizophrenia.

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Model for miRNA-associated dysregulation of synaptic structure and function in schizophrenia. The microprocessor activity is elevated in cortical nuclei as a consequence of a schizophrenia-associated increase in DGCR8 expression. The increase in pri-miRNA processing results in an increase in pre-miRNAs, which are exported from the nucleus and processed without delay by Exportin-5 (XPO5) and Dicer, respectively. Mature miRNAs are recruited into the RNA-induced silencing complex (RISC) and associate with the 3′-UTR of their target transcripts encoding synaptic components (among other proteins), such as neurotropins/ligands (BDNF, Reelin), neurotransmitter receptors (GRM7, GRIN3A, HTR2A, DRD1) and structural components of the post-synaptic density (DLG4). This association reduces the stability of the transcript and reduces its ability to undergo translation. Inappropriate levels of mature miRNA and gene silencing (red arrow) result in the reduction of synaptic proteins and consequently a loss of synaptic structure and function.
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fig5: Model for miRNA-associated dysregulation of synaptic structure and function in schizophrenia. The microprocessor activity is elevated in cortical nuclei as a consequence of a schizophrenia-associated increase in DGCR8 expression. The increase in pri-miRNA processing results in an increase in pre-miRNAs, which are exported from the nucleus and processed without delay by Exportin-5 (XPO5) and Dicer, respectively. Mature miRNAs are recruited into the RNA-induced silencing complex (RISC) and associate with the 3′-UTR of their target transcripts encoding synaptic components (among other proteins), such as neurotropins/ligands (BDNF, Reelin), neurotransmitter receptors (GRM7, GRIN3A, HTR2A, DRD1) and structural components of the post-synaptic density (DLG4). This association reduces the stability of the transcript and reduces its ability to undergo translation. Inappropriate levels of mature miRNA and gene silencing (red arrow) result in the reduction of synaptic proteins and consequently a loss of synaptic structure and function.

Mentions: Experiments in animal systems may also provide important insight into the behavioral consequences of altered cortical miRNA expression. In a recent study, mice treated with the NMDA receptor antagonist MK801 and hypomorphic GRIN1 (NR1) mutants showed a marked decrease in miR-219 expression.42 CaMKIIγ, a predicted target gene for this miRNA involved in NMDA signaling, was shown to be sensitive to miR-219 concentration in vitro. Moreover, suppression of miR-219 expression via intraventricular delivery of the corresponding LNA-modified anti-miR restored MK801 induced neurobehavioral dysfunction back to levels approaching that of the controls.42 Interestingly, in our study miR-219 was the most highly upregulated miRNA in the DLPFC and, in addition to the miR-15 family-related miRNA, could also be mediating a schizophrenia-associated reduction in NMDA signaling. These observations add support to the idea that these altered miRNAs are influential in the regulation of schizophrenia-associated genes and provide the basis of a model for the influence of disease-related miRNAs on genes involved in synaptic structure and function (Figure 5).


Schizophrenia is associated with an increase in cortical microRNA biogenesis.

Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ - Mol. Psychiatry (2009)

Model for miRNA-associated dysregulation of synaptic structure and function in schizophrenia. The microprocessor activity is elevated in cortical nuclei as a consequence of a schizophrenia-associated increase in DGCR8 expression. The increase in pri-miRNA processing results in an increase in pre-miRNAs, which are exported from the nucleus and processed without delay by Exportin-5 (XPO5) and Dicer, respectively. Mature miRNAs are recruited into the RNA-induced silencing complex (RISC) and associate with the 3′-UTR of their target transcripts encoding synaptic components (among other proteins), such as neurotropins/ligands (BDNF, Reelin), neurotransmitter receptors (GRM7, GRIN3A, HTR2A, DRD1) and structural components of the post-synaptic density (DLG4). This association reduces the stability of the transcript and reduces its ability to undergo translation. Inappropriate levels of mature miRNA and gene silencing (red arrow) result in the reduction of synaptic proteins and consequently a loss of synaptic structure and function.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2990188&req=5

fig5: Model for miRNA-associated dysregulation of synaptic structure and function in schizophrenia. The microprocessor activity is elevated in cortical nuclei as a consequence of a schizophrenia-associated increase in DGCR8 expression. The increase in pri-miRNA processing results in an increase in pre-miRNAs, which are exported from the nucleus and processed without delay by Exportin-5 (XPO5) and Dicer, respectively. Mature miRNAs are recruited into the RNA-induced silencing complex (RISC) and associate with the 3′-UTR of their target transcripts encoding synaptic components (among other proteins), such as neurotropins/ligands (BDNF, Reelin), neurotransmitter receptors (GRM7, GRIN3A, HTR2A, DRD1) and structural components of the post-synaptic density (DLG4). This association reduces the stability of the transcript and reduces its ability to undergo translation. Inappropriate levels of mature miRNA and gene silencing (red arrow) result in the reduction of synaptic proteins and consequently a loss of synaptic structure and function.
Mentions: Experiments in animal systems may also provide important insight into the behavioral consequences of altered cortical miRNA expression. In a recent study, mice treated with the NMDA receptor antagonist MK801 and hypomorphic GRIN1 (NR1) mutants showed a marked decrease in miR-219 expression.42 CaMKIIγ, a predicted target gene for this miRNA involved in NMDA signaling, was shown to be sensitive to miR-219 concentration in vitro. Moreover, suppression of miR-219 expression via intraventricular delivery of the corresponding LNA-modified anti-miR restored MK801 induced neurobehavioral dysfunction back to levels approaching that of the controls.42 Interestingly, in our study miR-219 was the most highly upregulated miRNA in the DLPFC and, in addition to the miR-15 family-related miRNA, could also be mediating a schizophrenia-associated reduction in NMDA signaling. These observations add support to the idea that these altered miRNAs are influential in the regulation of schizophrenia-associated genes and provide the basis of a model for the influence of disease-related miRNAs on genes involved in synaptic structure and function (Figure 5).

Bottom Line: MicroRNA expression profiling and quantitative reverse transcription-PCR analysis of the superior temporal gyrus and the dorsolateral prefrontal cortex revealed a significant schizophrenia-associated increase in global microRNA expression.This change was associated with an elevation of primary microRNA processing and corresponded with an increase in the microprocessor component DGCR8.The biological implications for this extensive increase in gene silencing are profound, and were exemplified by members of the miR-15 family and other related microRNA, which were significantly upregulated in both brain regions.

View Article: PubMed Central - PubMed

Affiliation: Schizophrenia Research Institute, Sydney, NSW, Australia.

ABSTRACT
MicroRNA expression profiling and quantitative reverse transcription-PCR analysis of the superior temporal gyrus and the dorsolateral prefrontal cortex revealed a significant schizophrenia-associated increase in global microRNA expression. This change was associated with an elevation of primary microRNA processing and corresponded with an increase in the microprocessor component DGCR8. The biological implications for this extensive increase in gene silencing are profound, and were exemplified by members of the miR-15 family and other related microRNA, which were significantly upregulated in both brain regions. This functionally convergent influence is overrepresented in pathways involved in synaptic plasticity and includes many genes and pathways associated with schizophrenia, some of which were substantiated in vitro by reporter gene assay. Given the magnitude of microRNA changes and their wide sphere of influence, this phenomenon could represent an important dimension in the pathogenesis of schizophrenia.

Show MeSH
Related in: MedlinePlus