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Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model

Abstract

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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Figure 1: Df(16)A+/− mice are hyperactive and show deficits in sensorimotor gating and two learning tasks.
Figure 2: Transcriptome alterations in the PFC and hippocampus of Df(16)A+/− mice.
Figure 3: miRNA biogenesis alterations in the PFC and hippocampus (HPC) of Df(16)A+/− mice.
Figure 4: Production, validation and analysis of miRNA biogenesis in Dgcr8-deficient mice.
Figure 5: Dgcr8 deficiency results in behavioral deficits.
Figure 6: Dgcr8 deficiency affects spine development and dendritic complexity.

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Acknowledgements

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.).

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Authors and Affiliations

Authors

Contributions

K.L.S., A.B., H.L. and A.A.M. contributed to the generation of the Df16(A)+/− line; K.L.S., B.X. and W.-S.L. performed the behavioral assays; B.X. and R.H. contributed to the generation and validation of the Dgcr8+/− line; B.X. performed the mRNA and miRNA expression analysis and the dendritic spine and complexity analysis; X.W. and P.P. contributed to the bioinformatic analysis of the mRNA expression data; M.K. and J.A.G. contributed to the research design and supervised the project.

Corresponding authors

Correspondence to Maria Karayiorgou or Joseph A Gogos.

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Supplementary Figures 1–4, Supplementary Tables 1–5, Supplementary Note and Supplementary Methods (PDF 1440 kb)

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Stark, K., Xu, B., Bagchi, A. et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet 40, 751–760 (2008). https://doi.org/10.1038/ng.138

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