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Sox8, Sox9 and Sox10 are a group of three closely related transcription factors that belong to the Sox protein family and jointly form the SoxE subgroup in vertebrates . Invertebrates have only a single SoxE protein. 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.
Sox8 is widely expressed throughout many tissues of mesodermal, neuroectodermal and neural crest origin . It is coexpressed with Sox9 in mesenchymal condensations, during chondrocyte development, in the developing male gonad, the forming outflow tract of the heart and the ventricular zone of the central nervous system (CNS). With Sox10 it shares common expression sites in developing oligodendrocytes of the CNS and many neural crest derivatives such as enteric nervous system and adrenal medulla. Sox8 expression is usually turned off once cells have matured and is generally indicative of an immature state.
Whereas Sox9 and Sox10 are essential for the generation of several cell types and tissues, Sox8 is dispensable for embryonic development as Sox8-deficient mice are born alive and in normal ratios . Compound mouse mutants, however, revealed that Sox8 supports Sox9 and Sox10 in their respective functions during development of the male gonad, the adrenal medulla, the enteric nervous system and during specification and terminal differentiation of oligodendrocytes in the CNS . The lesser influence of Sox8 on these developmental processes can be partly explained by lower expression levels . However, Sox8 and the other SoxE proteins are also not functionally equivalent, as replacement of Sox10 by Sox8 in the mouse did not fully rescue the typical defects of a Sox10-deficiency . The relative functional importance of SoxE proteins for a specific developmental process may also vary between different species. Sox8 has, for instance, been shown to have little impact on neural crest formation in mammals. In contrast, it is the most upstream and essential SoxE protein for neural crest formation in amphibians .
Postnatally, Sox8 deficient mice develop a low bone mass phenotype, lipodystrophy and progressive male infertility pointing to additional and non-redundant functions of Sox8 in osteoblasts, adipocytes and Sertoli cells of the adult .
Similar to other Sox proteins, Sox8 usually functions in cooperation with other transcription factors, and its activity is strongly influenced by its interaction partners . 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 .
- Guth SI and Wegner M. Having it both ways: Sox protein function between conservation and innovation. Cell. Mol. Life Sci., 65(19):3000-18. (PMID 18516494)
- 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)
- Pfeifer D et al. The SOX8 gene is located within 700 kb of the tip of chromosome 16p and is deleted in a patient with ATR-16 syndrome. Genomics, 63(1):108-16. (PMID 10662550)
- Schepers GE et al. Cloning and characterisation of the Sry-related transcription factor gene Sox8. Nucleic Acids Res., 28(6):1473-80. (PMID 10684944)
- Barrionuevo F et al. Testis cord differentiation after the sex determination stage is independent of Sox9 but fails in the combined absence of Sox9 and Sox8. Dev. Biol., 327(2):301-12. (PMID 19124014)
- Chaboissier MC et al. Functional analysis of Sox8 and Sox9 during sex determination in the mouse. Development, 131(9):1891-901. (PMID 15056615)
- Reiprich S et al. SoxE proteins are differentially required in mouse adrenal gland development. Mol. Biol. Cell, 19(4):1575-86. (PMID 18272785)
- Maka M et al. Identification of Sox8 as a modifier gene in a mouse model of Hirschsprung disease reveals underlying molecular defect. Dev. Biol., 277(1):155-69. (PMID 15572147)
- Stolt CC et al. Impact of transcription factor Sox8 on oligodendrocyte specification in the mouse embryonic spinal cord. Dev. Biol., 281(2):309-17. (PMID 15893981)
- Stolt CC et al. Transcription factors Sox8 and Sox10 perform non-equivalent roles during oligodendrocyte development despite functional redundancy. Development, 131(10):2349-58. (PMID 15102707)
- Kellerer S et al. Replacement of the Sox10 transcription factor by Sox8 reveals incomplete functional equivalence. Development, 133(15):2875-86. (PMID 16790476)
- O'Donnell M et al. Functional analysis of Sox8 during neural crest development in Xenopus. Development, 133(19):3817-26. (PMID 16943273)
- Schmidt K et al. The high mobility group transcription factor Sox8 is a negative regulator of osteoblast differentiation. J. Cell Biol., 168(6):899-910. (PMID 15753123)
- O'Bryan MK et al. Sox8 is a critical regulator of adult Sertoli cell function and male fertility. Dev. Biol., 316(2):359-70. (PMID 18342849)
- Guth SI et al. Adult-onset degeneration of adipose tissue in mice deficient for the Sox8 transcription factor. J. Lipid Res., 50(7):1269-80. (PMID 19286648)
- Wissmüller S et al. The high-mobility-group domain of Sox proteins interacts with DNA-binding domains of many transcription factors. Nucleic Acids Res., 34(6):1735-44. (PMID 16582099)
- 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)
FIGURE 1 Schematic representation of mouse Sox8
Its DNA-dependent dimerization domain (Dim), the DNA-binding HMG domain, the K2 domain and the transactivation domain (TA) are highly converved in Sox9 and Sox10. Numbers indicate amino acid positions. Sumoylation has been reported to occur on lysines 229 and 351 (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 Sox9 or Sox10 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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