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Author Notes:

Correspondence: Lan Xiao (xiaolan35@hotmail.com) Yue Feng (yfeng@emory.edu)

The authors declare that they have no competing financial interests.

Subject:

Research Funding:

This work was supported by NIH R01NS093016, NS070526 and NS056097 to Y.F.; NNSFC grant (31671117) and CSTCKJCXLJRC07 to L.X.; China Scholarship Council support (201403170254) to C.X.; NNSFC grant (31471955) to Z.X.; and Emory start-up fund to Z.W.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Psychiatry
  • HISTONE DEACETYLASE ACTIVITY
  • PROGENITOR DIFFERENTIATION
  • BINDING PARTNERS
  • CANDIDATE GENE
  • WHITE-MATTER
  • MUTANT MICE
  • RAT-BRAIN
  • HUMAN QKI
  • DISORDERS
  • EXPRESSION

Novel schizophrenia risk factor pathways regulate FEZ1 to advance oligodendroglia development

Tools:

Journal Title:

Translational Psychiatry

Volume:

Volume 7, Number 12

Publisher:

, Pages 1293-1293

Type of Work:

Article | Final Publisher PDF

Abstract:

Neuropsychiatric disorders, represented by schizophrenia, affect not only neurons but also myelinating oligodendroglia (OL), both contribute to the complex etiology. Although numerous susceptibility genes for schizophrenia have been identified, their function has been primarily studied in neurons. Whether malfunction of risk genes underlies OL defects in schizophrenia pathogenesis remains poorly understood. In this study, we investigated the function and regulation of the well-recognized schizophrenia risk factor, Fasciculation and Elongation Protein Zeta-1 (FEZ1), in OL. We found that FEZ1 is expressed in oligodendroglia progenitor cells (OPCs) derived from rodent brains and human induced pluripotent stem cells (iPSCs) in culture and in myelinating oligodendrocytes in the brain. In addition, a vigorous upregulation of FEZ1 occurs during OPC differentiation and myelinogenesis, whereas knockdown of FEZ1 significantly attenuates the development of OL process arbors. We further showed that transcription of the Fez1 gene in OL cells is governed by a sophisticated functional interplay between histone acetylation-mediated chromatin modification and transcription factors that are dysregulated in schizophrenia. At the post-transcriptional level, the selective RNA-binding protein QKI, a glia-specific risk factor of schizophrenia, binds FEZ1 mRNA. Moreover, QKI deficiency results in a marked reduction of FEZ1 specifically in OL cells of the quakingviable (qk v ) hypomyelination mutant mice. These observations have uncovered novel pathways that involve multifaceted genetic lesions and/or epigenetic dysregulations in schizophrenia, which converge on FEZ1 regulation and cause OL impairment in neuropsychiatric disorders.

Copyright information:

© 2017 The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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