Resolving the transcriptional transitions associated with oligodendrocyte generation from adult neural stem cells by single cell sequencing

Abstract

The subventricular zone (SVZ) is the largest neurogenic niche in the adult forebrain. Notably, neural stem cells (NSCs) of the SVZ generate not only neurons, but also oligodendrocytes, the myelin-forming cells of the central nervous system. Transcriptomic studies have provided detailed knowledge of the molecular events that regulate neurogenesis, but little is understood about adult oligodendrogenesis from SVZ-NSCs. To address this, we performed in-depth single-cell transcriptomic analyses to resolve the major differences in neuronal and oligodendroglial lineages derived from the adult SVZ. A hallmark of adult oligodendrogenesis was the stage-specific expression of transcriptional modulators that regulate developmental oligodendrogenesis. Notably, divergence of the oligodendroglial lineage was distinguished by Wnt-Notch and angiogenesis-related signaling, whereas G-protein-coupled receptor signaling pathways were the major signature observed in the neurogenic lineage. Moreover, in-depth gene regulatory network analysis identified key stage-specific master regulators of the oligodendrocyte lineage and revealed new mechanisms by which signaling pathways interact with transcriptional networks to control lineage progression. Our work provides an integrated view of the multi-step differentiation process leading from NSCs to mature oligodendrocytes, by linking environmental signals to known and novel transcriptional mechanisms orchestrating oligodendrogenesis. Main pointsO_LIDistinct adult NSC populations giving rise to either oligodendrocytes or neurons can be identified by the expression of transcription factors. C_LIO_LIGene regulatory control of oligodendrogenesis is a major fate-determinant for their generation. C_LI