Sox10 directs neural stem cells toward the oligodendrocyte lineage by decreasing Suppressor of Fused expression

Abstract

Oligodendrocyte precursor cells (OPCs) are lineage-restricted progenitors generally limited in vivo to producing oligodendrocytes. Mechanisms controlling genesis of OPCs are of interest because of their importance in myelin development and their potential for regenerative therapies in multiple sclerosis and dysmyelinating syndromes. We show here that the SoxE transcription factors (comprising Sox8, 9, and 10) induce multipotent neural precursor cells (NPCs) from the early postnatal subventricular zone (SVZ) to become OPCs in an autonomous manner. We performed a chromatin immunoprecipitation-based bioinformatic screen and identified Suppressor of Fused (Sufu) as a direct target of repression by Sox10. In vitro, overexpression of Sufu blocked OPC production, whereas RNAi-mediated inhibition augmented OPC production. Furthermore, mice heterozygous for Sufu have increased numbers of OPCs in the telencephalon during development. We conclude that Sox10 acts to restrict the potential of NPCs toward the oligodendrocyte lineage in part by regulating the expression of Sufu.

Transcription factor induction of human oligodendrocyte progenitor fate and differentiation

“…The induction of oligodendrocyte fate by individual TF overexpression has been studied in several model organisms, including zebrafish, chick, and mouse. It appears that multiple TFs can induce oligodendrocyte differentiation from neural precursors, including OLIG1/2, NKX2.2, ASCL1, SOX10, SOX17, and others (17,(27)(28)(29)(30)(31)(32)(33)(34); however, the instructive role of individual factors toward oligodendrocyte fate has not been observed consistently across species and systems. For example, ASCL1 is capable of inducing rapid oligodendrocyte differentiation in cultured mouse neural stem/progenitors (17), but retroviral-mediated expression in embryonic mouse forebrain does not induce oligodendrocyte fate (32).…”

Identification of GLI Mutations in Patients With Hirschsprung Disease That Disrupt Enteric Nervous System Development in Mice

“…Intriguingly, Sox10 has been shown to promote glial differentiation of CNS progenitors by down-regulating Sufu expression 20 . This raises the possibility that Sufu/Gli work together with Sox10 to determine the fate of NCCs.…”

Sox proteins: regulators of cell fate specification and differentiation

“…During the late stages of neural development, Sox9 regulates gliogenesis in neural stem cells (Stolt et al, 2003) using NFIA as its partner protein (Kang et al, 2012). Within the glial cells, oligodendrocyte development is redundantly supported by co-expressed Sox9 and Sox10 (Stolt et al, 2003), which repress suppressor of fused (Sufu) expression (Pozniak et al, 2010). …”