Sox10 cooperates with the mediator subunit 12 during terminal differentiation of myelinating glia.

Several transcription factors are essential for terminal differentiation of myelinating glia, among them the high-mobility-group-domain-containing 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.

SoxD proteins influence multiple stages of oligodendrocyte development and modulate SoxE protein function.

The myelin-forming oligodendrocytes are an excellent model to study transcriptional regulation of specification events, lineage progression, and terminal differentiation in the central nervous system. Here, we show that the group D Sox transcription factors Sox5 and Sox6 jointly and cell-autonomously regulate several stages of oligodendrocyte development in the mouse spinal cord. They repress specification and terminal differentiation and influence migration patterns. As a consequence, oligodendrocyte precursors and terminally differentiating oligodendrocytes appear precociously in spinal cords deficient for both Sox proteins. Sox5 and Sox6 have opposite functions than the group E Sox proteins Sox9 and Sox10, which promote oligodendrocyte specification and terminal differentiation. Both genetic as well as molecular evidence suggests that Sox5 and Sox6 directly interfere with the function of group E Sox proteins. Our studies reveal a complex regulatory network between different groups of Sox proteins that is essential for proper progression of oligodendrocyte development.

The high-mobility-group domain of Sox proteins interacts with DNA-binding domains of many transcription factors.

Sox proteins are widely believed to team up with other transcription factors as partner proteins to perform their many essential functions during development. In this study, yeast two-hybrid screens identified transcription factors as a major group of interacting proteins for Sox8 and Sox10. Interacting transcription factors were very similar for these two group E Sox proteins and included proteins with different types of DNA-binding domains, such as homeodomain proteins, zinc finger proteins, basic helix-loop-helix and leucine zipper proteins. In all cases analyzed, the interaction involved the DNA-binding domain of the transcription factor which directly contacted the C-terminal part of the high-mobility-group (HMG) domain. In particular, the C-terminal tail region behind helix 3 of the HMG domain was shown by mutagenesis to be essential for interaction and transcription factor recruitment. The HMG domain thus not only possesses DNA-binding and DNA-bending but also protein-interacting ability which may be equally important for the architectural function of Sox proteins on their target gene promoters.

The high-mobility group transcription factor Sox10 interacts with the N-myc-interacting protein Nmi.

The high-mobility group transcription factor Sox10 exerts many different roles during development of the neural crest and nervous system. To unravel its complex transcriptional functions, we have started to look for interaction partners. Here, we identify an association of Sox10 with the N-myc interactor Nmi, which was mediated by the high-mobility group of Sox10 and the central region of Nmi. In vivo relevance of this interaction is indicated by the fact that both proteins were co-expressed in glial cells, gliomas and in the spinal cord. Additionally, subcellular localization of Nmi in C6 glioma depended on the presence of Sox10 such that nuclear Nmi was more frequent in Sox10-expressing cells. Importantly, Nmi modulated the transcriptional activity of Sox10 in reporter gene assays. Nmi effects varied between different Sox10 target gene promoters, indicating that Nmi function in vivo may be promoter-specific.

Chromatin-remodeling factor Brg1 is required for Schwann cell differentiation and myelination.

Schwann cells produce myelin sheaths and thereby permit rapid saltatory conductance in the vertebrate peripheral nervous system. Their stepwise differentiation from neural crest cells is driven by a defined set of transcription factors. How this is linked to chromatin changes is not well understood. Here we show that the glial transcription factor Sox10 functions in Schwann cells by recruiting Brg1-containing chromatin-remodeling complexes via Baf60a to regulatory regions of Oct6 and Krox20 genes. It thereby stimulates expression of these transcriptional regulators that then cooperate with Sox10 to convert immature into myelinating Schwann cells. The functional interaction between Sox10 and Brg1 is evident from gain- and loss-of-function studies, similar neuropathies in the corresponding mouse mutants, and an aggravated neuropathy in compound mutants. Our results demonstrate that the transcription factor-mediated recruitment of the chromatin-remodeling machinery to specific genomic loci is an essential driving force for Schwann cell differentiation and myelination.