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 SklarManuel Mattheisen, David Cotter, Gang Fang, Kristen J. Brennand

Research output: Contribution to journalArticle

48 Citations (Scopus)

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. Topol et al. examine the role of decreased miR-9 levels in a subset of schizophrenia patient-derived neural progenitor cells from two independent cohorts. They observe a strong correlation between miR-9 expression and miR-9 regulatory activity. Manipulation of miR-9 impacts neural migration most likely through changes to many indirect miR-9 targets.

Original languageEnglish (US)
Pages (from-to)1024-1036
Number of pages13
JournalCell Reports
Volume15
Issue number5
DOIs
StatePublished - May 3 2016
Externally publishedYes

Fingerprint

MicroRNAs
Schizophrenia
Stem Cells
RNA Sequence Analysis
Set theory
Proteomics
Down-Regulation
Genes
RNA

Keywords

  • Human-induced pluripotent stem cell
  • MicroRNA-9
  • Neural progenitor cells
  • Schizophrenia

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Topol, A., Zhu, S., Hartley, B. J., English, J., Hauberg, M. E., Tran, N., ... Brennand, K. J. (2016). Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells. Cell Reports, 15(5), 1024-1036. https://doi.org/10.1016/j.celrep.2016.03.090

Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells. / Topol, Aaron; Zhu, Shijia; Hartley, Brigham J.; English, Jane; Hauberg, Mads E.; Tran, Ngoc; Rittenhouse, Chelsea Ann; Simone, Anthony; Ruderfer, Douglas M.; Johnson, Jessica; Readhead, Ben; Hadas, Yoav; Gochman, Peter A.; Wang, Ying Chih; Shah, Hardik; Cagney, Gerard; Rapoport, Judith; Gage, Fred H.; Dudley, Joel T.; Sklar, Pamela; Mattheisen, Manuel; Cotter, David; Fang, Gang; Brennand, Kristen J.

In: Cell Reports, Vol. 15, No. 5, 03.05.2016, p. 1024-1036.

Research output: Contribution to journalArticle

Topol, A, Zhu, S, Hartley, BJ, English, J, Hauberg, ME, Tran, N, Rittenhouse, CA, Simone, A, Ruderfer, DM, Johnson, J, Readhead, B, Hadas, Y, Gochman, PA, Wang, YC, Shah, H, Cagney, G, Rapoport, J, Gage, FH, Dudley, JT, Sklar, P, Mattheisen, M, Cotter, D, Fang, G & Brennand, KJ 2016, 'Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells', Cell Reports, vol. 15, no. 5, pp. 1024-1036. https://doi.org/10.1016/j.celrep.2016.03.090
Topol, Aaron ; Zhu, Shijia ; Hartley, Brigham J. ; English, Jane ; Hauberg, Mads E. ; Tran, Ngoc ; Rittenhouse, Chelsea Ann ; Simone, Anthony ; Ruderfer, Douglas M. ; Johnson, Jessica ; Readhead, Ben ; Hadas, Yoav ; Gochman, Peter A. ; Wang, Ying Chih ; Shah, Hardik ; Cagney, Gerard ; Rapoport, Judith ; Gage, Fred H. ; Dudley, Joel T. ; Sklar, Pamela ; Mattheisen, Manuel ; Cotter, David ; Fang, Gang ; Brennand, Kristen J. / Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells. In: Cell Reports. 2016 ; Vol. 15, No. 5. pp. 1024-1036.
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AU - Hauberg, Mads E.

AU - Tran, Ngoc

AU - Rittenhouse, Chelsea Ann

AU - Simone, Anthony

AU - Ruderfer, Douglas M.

AU - Johnson, Jessica

AU - Readhead, Ben

AU - Hadas, Yoav

AU - Gochman, Peter A.

AU - Wang, Ying Chih

AU - Shah, Hardik

AU - Cagney, Gerard

AU - Rapoport, Judith

AU - Gage, Fred H.

AU - Dudley, Joel T.

AU - Sklar, Pamela

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AU - Cotter, David

AU - Fang, Gang

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AB - 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. Topol et al. examine the role of decreased miR-9 levels in a subset of schizophrenia patient-derived neural progenitor cells from two independent cohorts. They observe a strong correlation between miR-9 expression and miR-9 regulatory activity. Manipulation of miR-9 impacts neural migration most likely through changes to many indirect miR-9 targets.

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