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Cell Rep. 2016 May 3;15(5):1024-1036. doi: 10.1016/j.celrep.2016.03.090. Epub 2016 Apr 21.

Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells.

Author information

1
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
2
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA.
3
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
4
Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Beaumont, Dublin 9, Ireland.
5
Department of Biomedicine and Centre for Integrative Sequencing (iSEQ), Aarhus University, Wilhelm Meyers Allé 4, Aarhus 8000 C, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Wilhelm Meyers Allé 4, Aarhus 8000 C, Denmark.
6
Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
7
Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
8
School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
9
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA. Electronic address: gang.fang@mssm.edu.
10
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA. Electronic address: kristen.brennand@mssm.edu.

Abstract

Converging evidence indicates that microRNAs (miRNAs) may contribute to disease risk for schizophrenia (SZ). We show that microRNA-9 (miR-9) is abundantly expressed in control neural progenitor cells (NPCs) but also significantly downregulated in a subset of SZ NPCs. We observed a strong correlation between miR-9 expression and miR-9 regulatory activity in NPCs as well as between miR-9 levels/activity, neural migration, and diagnosis. Overexpression of miR-9 was sufficient to ameliorate a previously reported neural migration deficit in SZ NPCs, whereas knockdown partially phenocopied aberrant migration in control NPCs. Unexpectedly, proteomic- and RNA sequencing (RNA-seq)-based analysis revealed that these effects were mediated primarily by small changes in expression of indirect miR-9 targets rather than large changes in direct miR-9 targets; these indirect targets are enriched for migration-associated genes. Together, these data indicate that aberrant levels and activity of miR-9 may be one of the many factors that contribute to SZ risk, at least in a subset of patients.

KEYWORDS:

human-induced pluripotent stem cell; microRNA-9; neural progenitor cells; schizophrenia

PMID:
27117414
PMCID:
PMC4856588
DOI:
10.1016/j.celrep.2016.03.090
[Indexed for MEDLINE]
Free PMC Article

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