Novel schizophrenia risk factor pathways regulate FEZ1 to advance oligodendroglia development

Xianjun Chen, Li Ku, Ruyi Mei, Guanglu Liu, Chongchong Xu, Zhexing Wen, Xiaofeng Zhao, Fei Wang, Lan Xiao, Yue Feng

Research output: Contribution to journalReview articlepeer-review

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 (qkv) 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.

Original languageEnglish (US)
Article number1293
JournalTranslational psychiatry
Volume7
Issue number12
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

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