| The hemizygous deletion of the 22q11.2 locus represents one of the highest known genetic risk factors for schizophrenia, second only to the risk posed by having an identical twin with the disease. Of the 35 genes in the 22q11.2 region, several have been previously identified as schizophrenia susceptibility genes, including PRODH, COMT, and ZDHHC8. In this study, we examine the contribution of two 22q11.2 positional candidate genes, RTN4R and DGCR8, to the genetic risk for schizophrenia and to the clinical expression of the disease.;RTN4R regulates axonal growth during development and after injury, and preliminary genetic studies have implicated RTN4R in modulating schizophrenia susceptibility. We performed a genetic association study in a large family-based sample and found weak sex-specific association between common RTN4R variants and schizophrenia. In an independent cohort, we screened for rare coding variants and identified two novel non-conservative RTN4R variants in schizophrenia patients that were absent in 600 control chromosomes. Complementary studies from an Rtn4r-deficient mouse model revealed a dosage-dependent locomotory effect but no discernible phenotype in a panel of schizophrenia-related behavioral assays. Furthermore, Rtn4r hypofunction was found to mediate the long-term locomotory effects of transient postnatal NMDAR blockade. We speculate that these locomotory domain-specific effects could contribute to the locomotory deficits reported in both 22q11DS and schizophrenia patients. Additional studies performed with DGCR8, a critical component of the miRNA processing pathway, identified a significant effect of miRNA biogenesis alterations on schizophrenia-related tasks. In a Dgcr8 -deficient mouse model, monoallelic loss of Dgcr8 resulted in deficits in spatial working memory and sensorimotor gating, as well as an abnormal dendritic morphology phenotype. MiRNA profiling of the brain revealed a selective downregulation of a subset of miRNAs in the heterozygous Dgcr8 mice. These deficits phenocopy a subset of those observed in a mouse strain containing a deletion of the syntenic 22q11.2 locus, suggesting that Dgcr8 haploinsufficiency contributes to the neurologic deficits induced by the 22q11DS chromosomal lesion. Our results provide in vivo evidence to support a role for normal miRNA biogenesis in regulating complex behaviors; in particular, we show that the disregulation of miRNAs may have a significant effect in modulating the cognitive and neuronal components of psychiatric disorders. |
