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Homo sapiens
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Mus musculus
Homo sapiens
Mus musculus
Transcription Factor Encyclopedia  BETA
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SOX9 is a member of the SRY-related HMG-box (SOX) gene family of transcription factors [1]. The high mobility group (HMG) box of the mammalian testis-determining factor SRY encodes for a DNA-binding domain which is conserved in all SOX proteins throughout the animal kingdom and binds to specific sequences in the minor groove of DNA [2]. SOX transcription factors interact with other co-factors to form nucleoprotein complexes and co-operative binding of these complexes results in sharp bending of the target DNA which is thought to be involved in chromatin remodelling and establishment of broad transcriptional programs [3] [4]. Furthermore, SOX proteins have been implicated in pre-mRNA splicing [5].

The HMG domain of SOX9 contains nuclear import and export sequences enabling functionally important shuttling of SOX9 protein between cytoplasm and nucleus [6] [7]. SOX9 belongs to the SoxE subgroup of SOX proteins including SOX8 and SOX10 which are structurally related by the presence of additional, conserved protein domains: an N-terminal dimerization domain, and two separate transactivation (TA) domains, one in the central position and one at the C terminus [2].

Sox9 is expressed in multiple tissues during mouse development [8] [9] and adulthood and its spatio- temporal expression pattern is regulated by a >2 Mb genomic region containing several evolutionary conserved, tissue-specific control elements [10]. Heterozygous loss-of-function mutations in the human SOX9 gene or chromosomal aberrations with breakpoints located hundreds of kilobases away from the SOX9 coding region cause the semilethal skeletal malformation syndrome campomelic dysplasia (CD) that is generally associated with male-to-female sex reversal and other variable organ defects [11] [12].

Functional studies in the mouse have identified essential roles for Sox9 during successive stages of cartilage formation [e.g. formation of mesenchymal cell condensations and chondrocyte differentiation [13] [14]] and during sex determination [e.g. testis cord formation and Sertoli cell differentiation [15] [16]] involving the regulation of diverse cellular processes such as condensation, proliferation, differentiation and apoptosis. Furthermore, several target genes of Sox9 including the direct targets collagen type II alpha 1 (Col2a1) [17] and anti-Mullerian hormone (Amh) [18] have been characterized and Sox9-regulated gene interaction networks have been defined [19] [20].

Sox9 has also been shown to control several important aspects during development and/or differentiation of glial cells [21], hair [22], heart [23] [24], intestinal epithelium [25], melanocytes [26], neural crest cells [27], notochord [28], otic placode [29], pancreas [30], prostate [31], pyloric sphincter [32] and retina [33]. However, in some other organ systems Sox9 function is redundant and possibly compensated by other Sox genes, especially the similarly expressed Sox8 and Sox10 [34] [35].

Despite the diverse functions of Sox9 in different tissues, common developmental features suggest that Sox9 may coordinate the balance between progenitor cell maintenance and differentiation into specialised cell types. This key regulatory function also indicates that abnormal SOX9 expression could be a predisposing factor for development of pre-malignant lesions. Although aberrant SOX9 expression has been reported in various types of cancer, it is currently not known if this is causally related to cancer formation [36].

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  2. Wegner M. From head to toes: the multiple facets of Sox proteins. Nucleic Acids Res., 27(6):1409-20. (PMID 10037800)
  3. Weiss MA. Floppy SOX: mutual induced fit in hmg (high-mobility group) box-DNA recognition. Mol. Endocrinol., 15(3):353-62. (PMID 11222737)
  4. Kamachi Y et al. Pairing SOX off: with partners in the regulation of embryonic development. Trends Genet., 16(4):182-7. (PMID 10729834)
  5. Ohe K et al. A direct role of SRY and SOX proteins in pre-mRNA splicing. Proc. Natl. Acad. Sci. U.S.A., 99(3):1146-51. (PMID 11818535)
  6. Smith JM and Koopman PA. The ins and outs of transcriptional control: nucleocytoplasmic shuttling in development and disease. Trends Genet., 20(1):4-8. (PMID 14698613)
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  8. Ng LJ et al. SOX9 binds DNA, activates transcription, and coexpresses with type II collagen during chondrogenesis in the mouse. Dev. Biol., 183(1):108-21. (PMID 9119111)
  9. Kent J et al. A male-specific role for SOX9 in vertebrate sex determination. Development, 122(9):2813-22. (PMID 8787755)
  10. Bagheri-Fam S et al. Long-range upstream and downstream enhancers control distinct subsets of the complex spatiotemporal Sox9 expression pattern. Dev. Biol., 291(2):382-97. (PMID 16458883)
  11. Wagner T et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell, 79(6):1111-20. (PMID 8001137)
  12. Pfeifer D et al. Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region. Am. J. Hum. Genet., 65(1):111-24. (PMID 10364523)
  13. Bi W et al. Sox9 is required for cartilage formation. Nat. Genet., 22(1):85-9. (PMID 10319868)
  14. Akiyama H et al. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev., 16(21):2813-28. (PMID 12414734)
  15. Chaboissier MC et al. Functional analysis of Sox8 and Sox9 during sex determination in the mouse. Development, 131(9):1891-901. (PMID 15056615)
  16. Barrionuevo F et al. Homozygous inactivation of Sox9 causes complete XY sex reversal in mice. Biol. Reprod., 74(1):195-201. (PMID 16207837)
  17. Bell DM et al. SOX9 directly regulates the type-II collagen gene. Nat. Genet., 16(2):174-8. (PMID 9171829)
  18. Arango NA et al. Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development. Cell, 99(4):409-19. (PMID 10571183)
  1. de Crombrugghe B et al. Regulatory mechanisms in the pathways of cartilage and bone formation. Curr. Opin. Cell Biol., 13(6):721-7. (PMID 11698188)
  2. Sekido R and Lovell-Badge R. Sex determination and SRY: down to a wink and a nudge? Trends Genet., 25(1):19-29. (PMID 19027189)
  3. 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)
  4. Vidal VP et al. Sox9 is essential for outer root sheath differentiation and the formation of the hair stem cell compartment. Curr. Biol., 15(15):1340-51. (PMID 16085486)
  5. Akiyama H et al. Essential role of Sox9 in the pathway that controls formation of cardiac valves and septa. Proc. Natl. Acad. Sci. U.S.A., 101(17):6502-7. (PMID 15096597)
  6. Lincoln J et al. Sox9 is required for precursor cell expansion and extracellular matrix organization during mouse heart valve development. Dev. Biol., 305(1):120-32. (PMID 17350610)
  7. Bastide P et al. Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium. J. Cell Biol., 178(4):635-48. (PMID 17698607)
  8. Passeron T et al. SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation. Proc. Natl. Acad. Sci. U.S.A., 104(35):13984-9. (PMID 17702866)
  9. Cheung M and Briscoe J. Neural crest development is regulated by the transcription factor Sox9. Development, 130(23):5681-93. (PMID 14522876)
  10. Barrionuevo F et al. Sox9 is required for notochord maintenance in mice. Dev. Biol., 295(1):128-40. (PMID 16678811)
  11. Barrionuevo F et al. Sox9 is required for invagination of the otic placode in mice. Dev. Biol., 317(1):213-24. (PMID 18377888)
  12. Seymour PA et al. SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc. Natl. Acad. Sci. U.S.A., 104(6):1865-70. (PMID 17267606)
  13. Thomsen MK et al. Sox9 is required for prostate development. Dev. Biol., 316(2):302-11. (PMID 18325490)
  14. Moniot B et al. SOX9 specifies the pyloric sphincter epithelium through mesenchymal-epithelial signals. Development, 131(15):3795-804. (PMID 15240557)
  15. Poché RA et al. Sox9 is expressed in mouse multipotent retinal progenitor cells and functions in Müller glial cell development. J. Comp. Neurol., 510(3):237-50. (PMID 18626943)
  16. Perl AK et al. Normal lung development and function after Sox9 inactivation in the respiratory epithelium. Genesis, 41(1):23-32. (PMID 15645446)
  17. Finzsch M et al. Sox9 and Sox10 influence survival and migration of oligodendrocyte precursors in the spinal cord by regulating PDGF receptor alpha expression. Development, 135(4):637-46. (PMID 18184726)
  18. Dong C et al. Sox genes and cancer. Cytogenet. Genome Res., 105(2-4):442-7. (PMID 15237232)
FIGURE 1 Schematic representation of the human SOX9 protein
The dimerization domain (DIM) precedes the DNA-binding/bending high mobility group domain (HMG) and two separate transactivation domains are located in a central position (K2) or at the C-terminus (TA). Whereas important roles for all these domains have been described, the function of the proline, glutamine and alanine-rich domain (PQA) is not known. The highly conserved amino acid sequence of the HMG domain is shown and two independent nuclear localisation sequences (NLS; basic residues are underlined) and the nuclear export sequence (NES) are highlighted. The position and the amino acid residues that are phosphorylated (brown) or sumoylated/ubiquitinated/acetylated (purple) are indicated.
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.