Regulation, function and evolutionary structure of St18, encoding a Zinc-Finger Transcription Factor, in the oligodendrocyte lineage

Abstract Myelinating oligodendrocytes are first observed during evolution in vertebrates above jawless fishes. Oligodendrocyte progenitor cells (OPCs) undergo extensive transcriptional and morphological remodelling to initiate differentiation and myelination. We report that the zinc-finger transcription factor St18 (aka Myt3) is upregulated during the OPC-to–newly formed oligodendrocyte (NFOL) transition. Single-nucleus RNA-sequencing (snRNA-seq) performed after lysolecithin-induced demyelination of the mouse spinal cord revealed that St18 was acutely upregulated in remyelinating OPCs. In primary rat OPC cultures, St18 overexpression promoted differentiation, whereas OPC conditional St18 knockout delayed developmental myelination in the mouse brain. Chromatin accessibility profiling identified candidate cis-regulatory elements for oligodendroglial St18 expression activated by core oligodendrocyte transcription factors, including SOX10, KLF9/13, and MYRF, and we confirmed that St18 expression in OPCs is Sox10-dependent in vivo. Phylogenetic analysis suggests that St18 arose via duplication of Myt1 in early jawed vertebrates, coinciding with the emergence of myelinating oligodendrocytes. These findings define St18 as a transcriptional marker of NFOLs and OLs and provide insight into the evolutionary regulation of central nervous system myelination.