Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells.
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.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
Aaron
A
Topol
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA.
Shijia
S
Zhu
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.
Brigham J
BJ
Hartley
Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Beaumont, Dublin 9, Ireland.
Jane
J
English
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.
Mads E
ME
Hauberg
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
Ngoc
N
Tran
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
Chelsea Ann
CA
Rittenhouse
Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Anthony
A
Simone
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
Douglas M
DM
Ruderfer
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
Jessica
J
Johnson
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA.
Ben
B
Readhead
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
Yoav
Y
Hadas
Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Peter A
PA
Gochman
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA.
Ying-Chih
YC
Wang
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA.
Hardik
H
Shah
School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
Gerard
G
Cagney
Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Judith
J
Rapoport
Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Fred H
FH
Gage
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, 1425 Madison Avenue, New York, NY 10029, USA.
Joel T
JT
Dudley
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
Pamela
P
Sklar
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.
Manuel
M
Mattheisen
Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Beaumont, Dublin 9, Ireland.
David
D
Cotter
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.
Gang
G
Fang
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.
Kristen J
KJ
Brennand
D016022:Case-Control Studies; D002465:Cell Movement / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D058977:Molecular Sequence Annotation; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D020543:Proteome / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism
C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D020543:Proteome; D014157:Transcription Factors
human-induced pluripotent stem cell; microRNA-9; neural progenitor cells; schizophrenia