The schizophrenia candidate gene MIR137: functional studies in mouse

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DESCRIPTION (provided by applicant): Schizophrenia (SCZ) is a complex and often devastating disease with a lifetime prevalence of 0.4%7 and heritability of ~80%.8 It is widely believed to be of neurodevelopmental origin.9, 10 There is now strong genetic evidence implicating the gene MIR137 and its microRNA (miRNA) product miR-137 in the etiology of SCZ. Association with this region has now reached 1.7x10-12 (N=59,318).1 14 genes have predicted or confirmed miR-137 target sites and genes with predicted miR-137 targets were significantly enriched for small GWAS p- values (p<0.01). In addition, miR-137 is implicated in neurodevelopment, Alzheimer's disease2, intellectual disability3, Huntington's disease,4 and mouse models of Rett syndrome.5 Therefore, miR-137 is a miRNA of important biological function and an intriguing candidate in SCZ and other neurological disease. We therefore propose to test the hypothesis that miR-137 is important for neuronal development in the mouse, identify pathways regulated by miR-137, and test whether these pathways play a role in the pathogenesis of SCZ. Using mice in which the Mir137 gene has been deleted, we will first characterize the mice for neurological or behavioral deficits. To address the role of miR-137 in proliferation and differentiation of neuronal cells, we will evaluate brain size and structure, neuronal density, neurogenesis, and dendritic complexity. miRNAs are known to directly regulate other RNAs through targeting for degradation or translational inhibition. Therefore, we will use an innovative combination of RNAseq and PAR-CLIP (an immunoprecipitation based method to identify RNAs bound by the miRNA regulation complex) to identify both direct and indirect targets of miR-137 in mouse brain. We will analyze these data to identify individual genes and biological pathways or networks influenced by miR-137. Finally, we will address whether the pathways and networks regulated by miR-137 are disrupted in SCZ by comparing to results from existing SCZ GWAS (PGC, >31,000 cases), exome sequencing (Sweden, 2500 cases), and post-mortem gene expression studies. These experiments will evaluate the role of miR-137 in the mouse brain, identify potential targets of miR-137 (both primary and secondary), and test for dysregulation of the miR-137 controlled pathway in SCZ. These results could provide functional evidence in support of a highly significant common risk factor for SCZ.