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Review
. 2010 Jun 18:1338:78-88.
doi: 10.1016/j.brainres.2010.03.109. Epub 2010 Apr 10.

MicroRNAs in psychiatric and neurodevelopmental disorders

Bin Xu  1 , Maria Karayiorgou, Joseph A Gogos
Affiliations
Review

MicroRNAs in psychiatric and neurodevelopmental disorders

Bin Xu et al. Brain Res. .

Abstract

Abnormalities in microRNA (miRNA)-mediated gene regulation have been observed in a variety of human diseases, especially in cancer. Here, we provide an account of newly emerging connections between miRNAs with various psychiatric and neurodevelopmental disorders, including recent findings of miRNA dysregulation in the 22q11.2 microdeletion syndrome, a well-established genetic risk factor for schizophrenia. miRNAs appear to be components of both the genetic architecture of these complex phenotypes as well as integral parts of the biological pathways that mediate the effects of primary genetic deficits. Therefore, they may contribute to both genetic heterogeneity and phenotypic variation of psychiatric and neurodevelopmental disorders and could serve as novel therapeutic targets.

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Figures

Figure 1
Figure 1. Components of miRNA biogenesis and mature miRNAs implicated in neural structure and function as well as in neuropsychiatric disorders and cognitive dysfunction
SCZ = schizophrenia, ASD = Autism spectrum disorder; FXS =Fragile X syndrome; RTT = Rett syndrome; DS = Down syndrome; TS = Tourette’s syndrome
Figure 2
Figure 2. Genomic structure of the human 1.5-Mb 22q11.2 locus and the syntenic mouse region and consequences of DGCR8 haploinsufficiency
Schematic diagram of the genomic structure of the 1.5-Mb human 22q11.2 microdeletion and the syntenic mouse region on chromosome 16. Almost all of the functional human genes in this segment are conserved in the mouse, organized in a slightly different order. The 1.5-Mb deletion is mediated by low copy repeat sequences LCR-A and LCR-B (illustrated as red boxes). PRODH-P and DGCR6-like indicate pseudogenes. Dgcr2 and Hira, the two endpoints of the targeted deletion of the mouse locus, are indicated by red arrowheads. The effect of DGCR8 haploinsufficiency on miRNA levels, CA1 pyramidal neuron dendritic morphology as well as behavior is summarized at the bottom. Hemizygosity of the Dgcr8 gene results in reduction in the levels of a subset of mature miRNAs in both prefrontal cortex and hippocampus. Partial reduction in miRNA levels can have an effect on transcript or protein levels of target genes. Moreover, since target mRNAs can be simultaneously and synergistically bound and repressed by more than one miRNA, the level of repression achieved may be highly sensitive to the amount of available miRNA complexes and the number of affected miRNAs. miRNA dysregulation is one of the molecular pathways affected in 22q11.2DS, is predicted to change the levels of several downstream target transcripts and proteins and results in a number of phenotypic alterations.
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