SOX10 Expression Levels may be a Critical Mediator of White Matter Dysfunction in Schizophrenia

Abstract: Abnormalities of brain connectivity are consistently observed in individuals with schizophrenias (SZ). Underlying these anomalies, convergent in vivo, post-mortem, and genomic evidence suggest abnormal oligodendrocyte (OL) development and function, including lower in vivo myelination in SZ. Using patient derived induced pluripotent stem cells (IPSCs), we previously observed a significant and substantial reduction in the number of OLs produced in cells from the SZ group compared to the healthy control (HC) group. We also observed a correlation between white matter (WM) estimated in brain in vivo and the number of OLs produced in vitro. We have now characterized potential mediators that may contribute to the SZ-associated deficit in OL production. We ran qRT-PCRs to detect group-specific differences in key myelin pathway proteins. Significant reductions of PAX6 and SOX10 expression were seen in the SZ group. We focused on SOX10 since one of its functions is the commitment of precursor cells to an oligodendrocyte fate. Using an inducible lentiviral system, we expressed SOX10 in patterned neural stem cells (NSCs) and quantified the number of OLs produced. Expression of SOX10 rescued the SZ-associated deficit in OL production, indicating that reduced SOX10 may be a critical mediator of OL dysfunction in SZ. We then ran qRT-PCRs to screen mRNAs for three proteins (SOX9, QK1 and FEZ1) whose expression was directly influenced by SOX10 or directly influenced the expression of SOX10. We saw significant reductions of SOX9 expression and a reduction in QK1 expression in the SZ group. RNAseq analysis confirmed these gene expression changes.