Individuals with 22q11.2 microdeletions show behavioral and cognitive deficits and are at high risk of developing schizophrenia. We analyzed an engineered mouse strain carrying a chromosomal deficiency spanning a segment syntenic to the human 22q11.2 locus. We uncovered a previously unknown alteration in the biogenesis of microRNAs (miRNAs) and identified a subset of brain miRNAs affected by the microdeletion. We provide evidence that the abnormal miRNA biogenesis emerges because of haploinsufficiency of the Dgcr8 gene, which encodes an RNA-binding moiety of the 'microprocessor' complex and contributes to the behavioral and neuronal deficits associated with the 22q11.2 microdeletion.
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We thank A. Merién for assistance with the dendritic complexity and spine analysis. We thank A. Abrams-Downey, C. Frazier, J. Pellegrino, D. Swor, Y. Sun and M. Sribour for technical support and assistance with the mouse colony. We also thank P.A. Arguello for help and insights with the behavioral assays. This research was supported in part by the US National Institutes of Health (grants MH067068 to M.K. and J.A.G. and MH077235 to J.A.G.) and the New York Academy of Sciences (J.A.G.). Support was also provided in part by a McKnight Brain Disorders award (J.A.G.) and a NARSAD award (J.A.G.), as well as an EJLB grant award (J.A.G.).