Functional Dissection of the Oct6 Schwann Cell Enhancer Reveals an Essential Role for Dimeric Sox10 Binding

Abstract

The POU domain transcription factor Pou3f1 (Oct6/Scip/Tst1) initiates the transition from ensheathing, promyelinating Schwann cells to myelinating cells. Axonal and other extra-cellular signals regulate Oct6 expression through the Oct6 Schwann cell enhancer (SCE), which is both required and sufficient to drive all aspects of Oct6 expression in Schwann cells. Thus, the Oct6 SCE is pivotal in the gene regulatory network that governs the onset of myelin formation in Schwann cells and provides a link between myelin promoting signalling and activation of a myelin related transcriptional network. In this study we define the relevant cis-acting elements within the SCE and identify the transcription factors that mediate Oct6 regulation. On the basis of phylogenetic comparisons and functional in vivo assays we identify a number of highly conserved core elements within the mouse SCE. We show that core element 1 is absolutely required for full enhancer function and that it contains closely-spaced inverted binding sites for Sox proteins. For the first time in vivo, the dimeric Sox10 binding to this element is shown to be essential for enhancer activity whereas monomeric Sox10 binding is non-functional. As Oct6 and Sox10 synergize to activate the expression of the major myelin-related transcription factor Krox20, we propose that Sox10 dependent activation of Oct6 defines a feed-forward regulatory module that serves to time and amplify the onset of myelination in the peripheral nervous system.

Desert Hedgehog Links Transcription Factor Sox10 to Perineurial Development

“…Similar to the other SoxE proteins Sox8 and Sox9, Sox10 can bind to DNA as monomer or dimer (Wegner, 2010), and it has been shown for at least two Sox10-responsive enhancers that a dimer site cannot simply be replaced by a monomer site without a significant loss in enhancer activity Jagalur et al, 2011). It has even been postulated that dimeric binding is such a crucial feature that it can be used to predict Sox10-dependent neural-crest enhancers (Antonellis et al, 2008).…”

“…For Schwann-cell-specific enhancers that are activated by Sox10, there seems to be no strict reliance on dimeric binding. Some Schwann-cell-specific enhancers only contain dimer sites and crucially depend on them (i.e., the Oct6 SCE) (Jagalur et al, 2011), whereas others contain only monomeric sites (i.e., the Dhh enhancer), yet others carry both monomeric and dimeric sites and need both for their activity (i.e., Krox20 myelinating Schwann cell enhancer, U3 enhancer of the Sox10 gene) (Reiprich et al, 2010;Wahlbuhl et al, 2012). Considering that Sox10 monomers affect the overall topology of the enhancer in a different way than dimers, the most likely explanation is that each enhancer contains the type of site that is best suited at its specific position to guarantee the multiprotein complex formation of the enhanceosome.…”

“…Two other Sox10 targets are the genes for the POU domain transcription factor Oct6 and the receptor tyrosine kinase subunit ErbB3 (Jagalur et al, 2011;Prasad et al, 2011). Oct6 is required for Schwann cells to progress to the pro-myelinating stage and to prepare for terminal differentiation (Bermingham et al, 1996;Jaegle et al, 1996), whereas ErbB3 acts as part of the ErbB2/ ErbB3 heterodimer that allows Schwann cells to respond in various phases of their development to neuregulin 1 (Newbern and Birchmeier, 2010).…”

Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity

“…Limpert and colleagues (2013) show that BrG1 interacts with NFkB to activate the Sox10 promoter and suggest that this mechanism controls BrG1-dependent SC 39]), the Krox20 MSE and the P0 promoter to induce Oct6, Krox20 and P0 expression [38][39][40], and thereby controls the myelination process.…”

“…Furthermore, while Sox10 levels are moderately [37] or not [38] affected in the absence of BrG1 in SCs, Oct6, Krox20 and P0 are virtually absent. Indeed, the BAF complex is recruited by Sox10 to the Oct6 SCE (SC enhancer [39]), the Krox20 MSE and the P0 promoter to induce Oct6, Krox20 and P0 expression [38][39][40], and thereby controls the myelination process.…”