Sox10 Cooperates with the Mediator Subunit 12 during Terminal Differentiation of Myelinating Glia

Abstract

Several transcription factors are essential for terminal differentiation of myelinating glia, among them the high-mobility-group-domaincontaining protein Sox10. To better understand how these factors exert their effects and shape glial expression programs, we identified and characterized a physical and functional link between Sox10 and the Med12 subunit of the Mediator complex that serves as a conserved multiprotein interphase between transcription factors and the general transcription machinery. We found that Sox10 bound with two of its conserved domains to the C-terminal region of Med12 and its close relative, Med12-like. In contrast to Med12-like, substantial amounts of Med12 were detected in both Schwann cells and oligodendrocytes. Its conditional glia-specific deletion in mice led to terminal differentiation defects that were highly reminiscent of those obtained after Sox10 deletion. In support of a functional cooperation, both proteins were jointly required for Krox20 induction and were physically associated with the critical regulatory region of the Krox20 gene in myelinating Schwann cells. We conclude that Sox10 functions during terminal differentiation of myelinating glia, at least in part by Med12-dependent recruitment of the Mediator complex.

Schwann cells and their transcriptional network: Evolution of key regulators of peripheral myelination

“…In addition to chromatin changes the eventual induction of Krox20 also depends on the Mediator complex and its Med12 subunit (Vogl et al, 2013). This subunit has been shown to physically associate with Sox10, bind to the MSE and functionally cooperate with Sox10 for MSE-dependent gene activation.…”

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

“…Mediator subunit 12 (Med12), as one of the kinase module subunits present in the mediator, and its paralog Med12-like were recently identified as interaction partners for Sox10 (Vogl et al, 2013). On the side of Sox10, this interaction was mapped to the combined dimerization and HMG domains as well as the transactivation domain (Figure 1).…”

Cyclin-dependent Kinase 8 Module Expression Profiling Reveals Requirement of Mediator Subunits 12 and 13 for Transcription of Serpent-dependent Innate Immunity Genes in Drosophila

“…In budding yeast, all four subunits control expression of a common set of genes (14), suggesting that Cdk8 has a major role. In mammalian cells, Cdk8 and Med12 sometimes cooperate on specific genes (15,16), but in other contexts Cdk8 and CycC appear to act independently of Med12, suggesting Mediator-independent functions (17,18). In Drosophila, effects of depletion of Cdk8 and CycC have been compared genome-wide in fat bodies where similar changes were noted (12).…”

“…Genome-wide analyses of the roles of all Cdk8 module subunits are lacking from metazoan cells. Dissecting these in mammalian cells is complicated by the partly redundant paralogs of Cdk8 (Cdk19 (22,23,24)), Med12 (Med12L (15,23)), and Med13 (Med13L (23,25)). Here we have utilized Drosophila cells to investigate whether the four Cdk8 module subunits regulate transcription in concert or independently genomewide.…”