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 SOX9
Homo sapiens
 HIF1A
Homo sapiens
 Pax6
Mus musculus
 PAX6
Homo sapiens
 Snai2
Mus musculus
 PPARA
Homo sapiens
 Ppara
Mus musculus
 Thrb
Mus musculus
 SNAI2
Homo sapiens
 Tbr1
Mus musculus
Transcription Factor Encyclopedia  BETA
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Overview

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[1]. 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)[2][3][4]. 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[3][5][2]. CNS myelination is additionally stalled[6]. 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[1]. 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[7][8], 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[9][10]. 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[11], thus confirming the importance of Sox10 for glial development in PNS and CNS. Sox10 functions are furthermore strongly conserved in all vertebrates[12][13]. 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[14]. 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[15].

References
  1. Wegner M and Stolt CC. From stem cells to neurons and glia: a Soxist's view of neural development. Trends Neurosci., 28(11):583-8. (PMID 16139372)
  2. Britsch S et al. The transcription factor Sox10 is a key regulator of peripheral glial development. Genes Dev., 15(1):66-78. (PMID 11156606)
  3. Southard-Smith EM et al. Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat. Genet., 18(1):60-4. (PMID 9425902)
  4. Kelsh RN. Sorting out Sox10 functions in neural crest development. Bioessays, 28(8):788-98. (PMID 16927299)
  5. Herbarth B et al. Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for human Hirschsprung disease. Proc. Natl. Acad. Sci. U.S.A., 95(9):5161-5. (PMID 9560246)
  6. Stolt CC et al. Terminal differentiation of myelin-forming oligodendrocytes depends on the transcription factor Sox10. Genes Dev., 16(2):165-70. (PMID 11799060)
  7. Taylor KM and Labonne C. SoxE factors function equivalently during neural crest and inner ear development and their activity is regulated by SUMOylation. Dev. Cell, 9(5):593-603. (PMID 16256735)
  8. Rehberg S et al. Sox10 is an active nucleocytoplasmic shuttle protein, and shuttling is crucial for Sox10-mediated transactivation. Mol. Cell. Biol., 22(16):5826-34. (PMID 12138193)
  1. Pingault V et al. SOX10 mutations in patients with Waardenburg-Hirschsprung disease. Nat. Genet., 18(2):171-3. (PMID 9462749)
  2. Touraine RL et al. Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain. Am. J. Hum. Genet., 66(5):1496-503. (PMID 10762540)
  3. Inoue K et al. Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat. Genet., 36(4):361-9. (PMID 15004559)
  4. Aoki Y et al. Sox10 regulates the development of neural crest-derived melanocytes in Xenopus. Dev. Biol., 259(1):19-33. (PMID 12812785)
  5. Dutton KA et al. Zebrafish colourless encodes sox10 and specifies non-ectomesenchymal neural crest fates. Development, 128(21):4113-25. (PMID 11684650)
  6. Sock E et al. Idiopathic weight reduction in mice deficient in the high-mobility-group transcription factor Sox8. Mol. Cell. Biol., 21(20):6951-9. (PMID 11564878)
  7. Hui Yong Loh S and Russell S. A Drosophila group E Sox gene is dynamically expressed in the embryonic alimentary canal. Mech. Dev., 93(1-2):185-8. (PMID 10781954)
Figures
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.