Protein Zero Gene Expression Is Regulated by the Glial Transcription Factor Sox10

Abstract

Myelinating glia express high levels of a unique set of genes which code for structural proteins of the myelin sheath. Few transcription factors have so far been implicated in the regulation of any myelin gene. Here we show that the protein zero (P 0 ) gene, a myelin gene exclusively expressed in the Schwann cell lineage of the peripheral nervous system, is controlled in its expression by the high-mobility-group domain protein Sox10 both in tissue culture and in vivo. Induction of wild-type Sox10, but not of other transcription factors or Sox10 mutants, strongly increased endogenous P 0 expression in tissue culture. This activation was mediated by the P 0 promoter, which was stimulated by Sox10 in transient transfections. Detailed analyses revealed the involvement of a proximal and a distal promoter region. The distal region functioned only in conjunction with the proximal one and contained a single Sox consensus binding site, which accounted for most of its activity. In contrast, the proximal region mediated Sox10 responsiveness on its own. It contained multiple binding sites for Sox proteins, with two high-affinity sites being the most significant. P 0 expression also depended on Sox10 in vivo, as evident from the analysis of Schwann cell precursors in mouse embryos with Sox10 mutation at day 12.5 of embryogenesis. To our knowledge this is the most conclusive link to date between a glial transcription factor and cell-specific activation of myelin gene expression.

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

“…This antiserum recognizes an epitope at amino acids 165-181 of human SOX10; therefore, the signals were quantitative for both wild-type SOX10 and the truncated proteins used in this study. We used oligonucleotide probes containing a single SOX10-binding site (site B) 43 for EMSAs.…”

Activation of Myelin Genes during Transdifferentiation from Melanoma to Glial Cell Phenotype

“…The B16/F10.9 cells express endogenous Sox10, an HMG factor found to be important in both melanocytic (45)(46)(47)(48) and SC differentiation (15,16,49). An increase in Sox10 RNA was observed by RT-PCR with RNA extracted 72 h after IL6RIL6 addition to the cells (Fig.…”

“…15 for review). Thus, the high mobility group (HMG) domain Sox10, already present in early neural crest cells, activates the Po promoter (16). Krox20/Egr2, a late marker of myelinating SC differentiation required for myelination (17), stimulates expression of several myelin genes (18,19).…”

Complementation of melanocyte development in SOX10 mutant neural crest using lineage‐directed gene transfer

“…The analysis of Sox10 gene function using mutant mammalian models is hampered because Sox10 Dom /Sox10 Dom and Sox10 LacZ /Sox10 LacZ embryos die before birth (Lane andLiu, 1984, Britsch et al, 2001). Although it has been demonstrated that Sox10 is critical for survival of several NC-derived lineages (Southard-Smith et al, 1998;Britsch et al, 2001;Potterf et al, 2001) and several downstream target genes have been identified Lang et al, 2000;Lee et al, 2000;Peirano et al, 2000;Potterf et al, 2000Potterf et al, , 2001Bondurand et al, 2001;Britsch et al, 2001), the functional roles of SOX10 in the development of NC-derived lineages is not completely understood.…”