Manuel Mattheisen

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Aaron Topol, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
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  • Shijia Zhu, Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA.
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  • Brigham J Hartley, 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.
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  • Jane English, Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Beaumont, Dublin 9, Ireland.
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  • Mads E Hauberg
  • Ngoc Tran, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
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  • Chelsea Ann Rittenhouse, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
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  • Anthony Simone, Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
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  • Douglas M Ruderfer, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
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  • Jessica Johnson, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
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  • Ben Readhead, Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA.
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  • Yoav Hadas, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
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  • Peter A Gochman, Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
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  • Ying-Chih Wang, Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA.
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  • Hardik Shah, Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA.
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  • Gerard Cagney, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
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  • Judith Rapoport, Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
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  • Fred H Gage, Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
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  • Joel T Dudley, Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA.
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  • Pamela Sklar, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
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  • Manuel Mattheisen
  • David Cotter, Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Beaumont, Dublin 9, Ireland.
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  • Gang Fang, 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.
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  • Kristen J Brennand, 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.

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.

Original languageEnglish
JournalCell Reports
Volume15
Issue5
Pages (from-to)1024-36
Number of pages13
ISSN2211-1247
DOIs
Publication statusPublished - 3 May 2016

    Research areas

  • Journal Article

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