Novel schizophrenia risk factor pathways regulate FEZ1 to advance oligodendroglia development

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Schizophrenia affects neurons and myelinating oligodendroglia (OL), but OL defects are poorly understood.
• Schizophrenia risk genes are primarily studied in neurons, leaving their role in OL dysfunction unclear.

Purpose of the Study:

• Investigate the function and regulation of schizophrenia risk factor Fasciculation and Elongation Protein Zeta-1 (FEZ1) in OL.
• Elucidate the role of FEZ1 in OL development and its connection to schizophrenia pathogenesis.

Main Methods:

• Assessed FEZ1 expression in cultured oligodendroglia progenitor cells (OPCs) and human iPSCs, and in brain tissue.
• Examined FEZ1's role in OL differentiation and process arbor development via knockdown experiments.
• Investigated Fez1 gene transcription regulation through histone acetylation and transcription factors.
• Studied the interaction between RNA-binding protein QKI and FEZ1 mRNA in OL cells and in quaking-viable mutant mice.

Main Results:

• FEZ1 is expressed in OPCs, iPSCs, and mature oligodendrocytes, with upregulation during differentiation and myelinogenesis.
• FEZ1 knockdown significantly impaired OL process arbor development.
• Fez1 transcription in OLs is regulated by epigenetic modifications and schizophrenia-associated transcription factors.
• The schizophrenia risk factor QKI binds FEZ1 mRNA, and QKI deficiency reduces FEZ1 levels in OLs of hypomyelination mutant mice.

Conclusions:

• FEZ1 plays a critical role in OL development and myelinogenesis.
• Dysregulation of FEZ1, through genetic and epigenetic mechanisms involving QKI, contributes to OL impairment in schizophrenia.
• Identified novel pathways linking genetic/epigenetic factors to OL dysfunction in neuropsychiatric disorders.