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Sox10, Sox9 and Sox8 are a group of three closely related transcription factors that belong to the Sox protein family and jointly form the SoxE subgroup. Like all HMG domain proteins, SoxE factors bind to the minor groove and introduce a strong bend into the DNA. They are therefore believed to exert structural roles on regulatory DNA regions. SoxE proteins furthermore show partially overlapping expression during development, with Sox9 and Sox10 functioning as major regulators in different cell types and tissues, and Sox8 supporting their function.
Sox10 expression is particularly prominent in early neural crest cells, different derivatives of the neural crest including glial cells of the peripheral nervous system (PNS), sympathetic and enteric nervous system, adrenal medulla and melanocytes, the otic epithelium and oligodendroglial cells of the central nervous system (CNS). Functional roles for Sox10 in all these cell types have been revealed by mutational analyses in the mouse. Sox10-deficient mice die at birth from PNS defects and lack the enteric nervous system and all melanocytes. CNS myelination is additionally stalled. Some of these defects become already apparent in mice with only a single functional Sox10 allele arguing for haploinsufficiency.
Similar to other Sox proteins, Sox10 usually functions in cooperation with other transcription factors, and its activity is strongly influenced by its interaction partners. This endows Sox10 with remarkable functional versatility. Known cell-type specific and context-dependent target genes include other transcription factors, receptor tyrosine kinases, but also determinants of a differentiated cell phenotype. Other factors influencing its activity are posttranslational modifications such as sumoylation and translocation between the nuclear and cytoplasmic compartment, although the link between these events and the signalling pathways that cause them are still poorly characterized.
SOX10 haploinsufficiency in humans leads to pigmentation defects and colonic aganglionosis and presents most frequently as Waardenburg-Hirschsprung disease (also called Waardenburg-Shah syndrome, WS4), sometimes however also as isolated Waardenburg disease (WS2) or Yemenite deaf-blind-hypopigmentation syndrome. Dominant SOX10 mutations on the other hand cause PCWH syndrome in humans in which Waardenburg-Hirschsprung disease symptoms are combined with additional peripheral neuropathies and central dysmyelination, thus confirming the importance of Sox10 for glial development in PNS and CNS. Sox10 functions are furthermore strongly conserved in all vertebrates. Essential roles during embryonic development have also been detected for Sox9, heterozygous mutations of which cause Campomelic Dysplasia in humans as well as male-to-female sex reversal. In contrast, loss of Sox8 has only mild phenotypic consequences. Sox10 and Sox9 thus largely compensate for the loss of Sox8, but not vice versa. Invertebrates have only a single SoxE protein, called Sox100B in Drosophila melanogaster.
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FIGURE 1 Schematic representation of mouse SOX10
Its DNA-dependent dimerization domain (Dim), the DNA-binding HMG domain, the K2 domain and the transactivation domain (TA) are highly converved in Sox8 and Sox9. Numbers indicate amino acid positions. Sumoylation has been reported to occur on lysines 55, 246 and 357 (blue ellipses). The bottom shows the exact amino acid sequence of the HMG domain with several hallmarks including the three alpha-helices, the 2 nuclear localization signals (NLS1, NLS2), and the nuclear export sequence (NES). Amino acids that are not fully conserved in the HMG domain of either Sox8 or Sox9 are highlighted by arrows.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.
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