Olig2 regulates Sox10 expression in oligodendrocyte precursors through an evolutionary conserved distal enhancer

Abstract

The HMG-domain transcription factor Sox10 is expressed throughout oligodendrocyte development and is an important component of the transcriptional regulatory network in these myelin-forming CNS glia. Of the known Sox10 regulatory regions, only the evolutionary conserved U2 enhancer in the distal 5′-flank of the Sox10 gene exhibits oligodendroglial activity. We found that U2 was active in oligodendrocyte precursors, but not in mature oligodendrocytes. U2 activity also did not mediate the initial Sox10 induction after specification arguing that Sox10 expression during oligodendroglial development depends on the activity of multiple regulatory regions. The oligodendroglial bHLH transcription factor Olig2, but not the closely related Olig1 efficiently activated the U2 enhancer. Olig2 bound U2 directly at several sites including a highly conserved one in the U2 core. Inactivation of this site abolished the oligodendroglial activity of U2 in vivo. In contrast to Olig2, the homeodomain transcription factor Nkx6.2 repressed U2 activity. Repression may involve recruitment of Nkx6.2 to U2 and inactivation of Olig2 and other activators by protein–protein interactions. Considering the selective expression of Nkx6.2 at the time of specification and in differentiated oligodendrocytes, Nkx6.2 may be involved in limiting U2 activity to the precursor stage during oligodendrocyte development.

Alu-mediated deletion of SOX10 regulatory elements in Waardenburg syndrome type 4

“…6 The deletion described here also encompassed the U2 regulatory element, which is known to be active in oligodendrocytes. However, this element is only partly responsible for the Sox10 expression pattern in this lineage, 14 making the absence of neurological defects observed in the patient consistent with our findings. Finally, the rearrangement also led to a partial heterozygous deletion of PICK1 (protein interacting with C kinase 1), encoding a peripheral membrane protein implicated in the trafficking of multiple proteins.…”

Transcription factor induction of human oligodendrocyte progenitor fate and differentiation

“…Interestingly, coinfection with SOX10 and OLIG2 viruses did not result in a significant increase in O4 + oligodendrocyte differentiation, suggesting that OLIG2 is not the sole limiting factor for OPC fate induction by SOX10. Indeed, because both binding partners (37) and phosphorylation state (38) can regulate the function of OLIG2, overexpression of OLIG2 alone might not provide the correct cellular context for induction of OPC fate.…”

Sox appeal – Sox10 attracts epigenetic and transcriptional regulators in myelinating glia

“…One of the most prominent oligodendrocyte-specific transcription factors is the bHLH protein oligodendrocyte lineage transcription factor 2 (Olig2). It is already responsible for OPC specification, continues to be expressed throughout oligodendroglial development and activates Sox10 transcription (Zhou et al, 2000;Lu et al, 2002;Zhou and Anderson, 2002;Küspert et al, 2011). Although a physical interaction between Olig2 and Sox10 has been detected (Wißmüller et al, 2006) (Figure 1) and although the long co-expression of both transcription factors during oligodendroglial development strongly argues for the functional importance of such an interaction, no joint target genes have been identified yet.…”

“…Even though the requirements for Sox10 differ somewhat, this transcription factor is an essential general determinant of myelination in both cell types. Considering its importance, it is not surprising that Sox10 expression is tightly controlled both on the epigenetic and on the transcriptional level (Iwamoto et al, 2005;Küspert et al, 2011). These aspects are, however, outside the focus of this review.…”