Transcription factor Sox10 orchestrates activity of a neural crest-specific enhancer in the vicinity of its gene

Abstract

The Sox10 transcription factor is a central regulator of vertebrate neural crest and nervous system development. Its expression is likely controlled by multiple enhancer elements, among them U3 (alternatively known as MCS4). Here we analyze U3 activity to obtain deeper insights into Sox10 function and expression in the neural crest and its derivatives. U3 activity strongly depends on the presence of Sox10 that regulates its own expression as commonly observed for important developmental regulators. Sox10 bound directly as monomer to at least three sites in U3, whereas a fourth site preferred dimers. Deletion of these sites efficiently reduced U3 activity in transfected cells and transgenic mice. In stimulating the U3 enhancer, Sox10 synergized with many other transcription factors present in neural crest and developing peripheral nervous system including Pax3, FoxD3, AP2α, Krox20 and Sox2. In case of FoxD3, synergism involved Sox10-dependent recruitment to the U3 enhancer, while Sox10 and AP2α each had to bind to the regulatory region. Our study points to the importance of autoregulatory activity and synergistic interactions for maintenance of Sox10 expression and functional activity of Sox10 in the neural crest regulatory network.

Establishing neural crest identity: a gene regulatory recipe

“…Furthermore, Sox10 was shown to directly regulate itself, consistent with its continuous expression in the migratory neural crest. This positive self-regulatory loop relies on synergistic activity with Tfap2a and FoxD3 (Wahlbuhl et al, 2012). That FoxD3 acts as a direct regulator of Sox10 in migratory cells is supported by another study that identified an intronic enhancer in the zebrafish sox10 locus, which contains FoxD3, Sox and LEF/TCF binding sites (Dutton et al, 2008).…”

Desert Hedgehog Links Transcription Factor Sox10 to Perineurial Development

“…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.…”

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

“…In vitro experiments indicate that deletion of this domain does not reduce the transactivation potential of Sox10, but may interfere with its ability to function synergistically with other transcription factors (Reiprich et al, 2008). This argues that the K2 domain likely functions as another interface for protein interactions, although the only interactor so far identified is AP2α (Figure 1) (Wahlbuhl et al, 2011). The last domain that is shared between SoxE proteins is the transactivation domain at the carboxyterminal end ( Figure 1).…”