Cell Reports (May 2016)
Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells
- Aaron Topol,
- Shijia Zhu,
- Brigham J. Hartley,
- Jane English,
- Mads E. Hauberg,
- Ngoc Tran,
- Chelsea Ann Rittenhouse,
- Anthony Simone,
- Douglas M. Ruderfer,
- Jessica Johnson,
- Ben Readhead,
- Yoav Hadas,
- Peter A. Gochman,
- Ying-Chih Wang,
- Hardik Shah,
- Gerard Cagney,
- Judith Rapoport,
- Fred H. Gage,
- Joel T. Dudley,
- Pamela Sklar,
- Manuel Mattheisen,
- David Cotter,
- Gang Fang,
- Kristen J. Brennand
Affiliations
- Aaron Topol
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
- Shijia Zhu
- Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA
- Brigham J. Hartley
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
- Jane English
- Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Beaumont, Dublin 9, Ireland
- Mads E. Hauberg
- Department of Biomedicine and Centre for Integrative Sequencing (iSEQ), Aarhus University, Wilhelm Meyers Allé 4, Aarhus 8000 C, Denmark
- Ngoc Tran
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
- Chelsea Ann Rittenhouse
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
- Anthony Simone
- Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
- Douglas M. Ruderfer
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
- Jessica Johnson
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
- Ben Readhead
- Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA
- Yoav Hadas
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
- Peter A. Gochman
- Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA
- Ying-Chih Wang
- Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA
- Hardik Shah
- Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA
- Gerard Cagney
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
- Judith Rapoport
- Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA
- Fred H. Gage
- Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
- Joel T. Dudley
- Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA
- Pamela Sklar
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
- Manuel Mattheisen
- Department of Biomedicine and Centre for Integrative Sequencing (iSEQ), Aarhus University, Wilhelm Meyers Allé 4, Aarhus 8000 C, Denmark
- David Cotter
- Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Beaumont, Dublin 9, Ireland
- Gang Fang
- Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA
- Kristen J. Brennand
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
- DOI
- https://doi.org/10.1016/j.celrep.2016.03.090
- Journal volume & issue
-
Vol. 15,
no. 5
pp. 1024 – 1036
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
