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Author Notes:

Correspondence and Lead Contact: gbassel@emory.edu (G.J.B.)

Author Contributions: K.T.T., B.R.A., and G.J.B. conceived of the study, designed experiments, and analyzed and interpreted data. K.T.T., B.R.A., N.S., S.E.Z., D.H., A.N.V., and Q.G. performed experiments and analyzed data.

We also thank Dr Armaz Aschrafi (NIMH) for generously providing the miR-137 sponge.

Subjects:

Research Funding:

This work was supported by 1R21NS089080 (GJB), 5T32MH087977 and 1F32NS083205 (BRA), 1F31NS087713-01 (KTT), and P30NS055077 (Viral Vector Core of the Emory Neuroscience NINDS Core Facilities grant).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • PREFRONTAL CORTEX
  • CORTICAL-NEURONS
  • HUMAN BRAIN
  • TRANSLATION
  • GROWTH
  • DEPRESSION
  • DENDRITES
  • DISEASES
  • TARGET
  • ALPHA
  • miR-137
  • Neuregulin
  • BDNF
  • Schizophrenia
  • mTOR
  • AMPAR

Inhibition of the Schizophrenia-Associated MicroRNA miR-137 Disrupts Nrg1 alpha Neurodevelopmental Signal Transduction

Tools:

Journal Title:

Cell Reports

Volume:

Volume 20, Number 1

Publisher:

, Pages 1-12

Type of Work:

Article | Final Publisher PDF

Abstract:

Genomic studies have repeatedly associated variants in the gene encoding the microRNA miR-137 with increased schizophrenia risk. Bioinformatic predictions suggest that miR-137 regulates schizophrenia-associated signaling pathways critical to neural development, but these predictions remain largely unvalidated. In the present study, we demonstrate that miR-137 regulates neuronal levels of p55γ, PTEN, Akt2, GSK3β, mTOR, and rictor. All are key proteins within the PI3K-Akt-mTOR pathway and act downstream of neuregulin (Nrg)/ErbB and BDNF signaling. Inhibition of miR-137 ablates Nrg1α-induced increases in dendritic protein synthesis, phosphorylated S6, AMPA receptor subunits, and outgrowth. Inhibition of miR-137 also blocks mTORC1-dependent responses to BDNF, including increased mRNA translation and dendritic outgrowth, while leaving mTORC1-independent S6 phosphorylation intact. We conclude that miR-137 regulates neuronal responses to Nrg1α and BDNF through convergent mechanisms, which might contribute to schizophrenia risk by altering neural development.

Copyright information:

© 2017 The Author(s)

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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