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Gene Review

SOX9  -  SRY (sex determining region Y)-box 9

Homo sapiens

Synonyms: CMD1, CMPD1, SRA1, Transcription factor SOX-9
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Disease relevance of SOX9


Psychiatry related information on SOX9

  • However, at FPT the expression of SOX9 protein decreases at stage 25 and disappears at stage 26, suggesting this as the critical period for SOX9 regulation by temperature [9].

High impact information on SOX9

  • SOX9 is a high-mobility-group (HMG) domain transcription factor that is expressed in chondrocytes and other tissues [10].
  • These results demonstrate that COL2A1 expression is directly regulated by SOX9 protein in vivo and implicate abnormal regulation of COL2A1 during, chondrogenesis as a cause of the skeletal abnormalities associated with campomelic dysplasia [11].
  • Sex reversal by loss of the C-terminal transactivation domain of human SOX9 [12].
  • We show in cell transfection experiments that SOX9 can transactivate transcription from a reporter plasmid through the motif AACAAAG, a sequence recognized by other HMG domain transcription factors [12].
  • Heterozygous mutations in SOX9 lead to a human dwarfism syndrome, Campomelic dysplasia [13].

Chemical compound and disease context of SOX9


Biological context of SOX9

  • Mutations in the human SRY-related gene, SOX9, located on chromosome 17, have recently been associated with the sex reversal and skeletal dysmorphology syndrome, campomelic dysplasia [17].
  • Mutation of these sequences abolishes SOX9 binding and chondrocyte-specific expression of a COL2A1-driven reporter gene (COL2A1-lacZ) in transgenic mice [11].
  • Cloning of a translocation chromosome breakpoint from a sex-reversed patient with campomelic dysplasia, followed by mutation analysis of an adjacent gene, indicates that SOX9, an SRY-related gene, is involved in both bone formation and control of testis development [18].
  • SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene [19].
  • Two functional domains are so far recognized for SOX9, a high-mobility group (HMG) DNA-binding domain and a C-terminal transactivation domain [20].

Anatomical context of SOX9

  • SOX9 encodes a putative transcription factor structurally related to the testis-determining factor SRY and is expressed in many adult tissues, and in fetal testis and skeletal tissue [21].
  • We provide in vitro and in vivo evidence that a bipartite beta-catenin/TCF4 transcription factor, the effector of the Wnt signaling pathway, is required for SOX9 expression in epithelial cells [22].
  • We report that the SOX9 protein is expressed in the intestinal epithelium in a pattern characteristic of Wnt targets [22].
  • Our results strongly suggest a model whereby SOX9 is involved in the control of the cell-specific activation of COL2A1 in chondrocytes, an essential component of the differentiation program of these cells [19].
  • Expression of a truncated SOX9 protein lacking the transactivation domain but retaining DNA-binding activity interferes with enhancer activation by full-length SOX9 in fibroblasts and inhibits enhancer activity in chondrocytes [19].

Associations of SOX9 with chemical compounds


Physical interactions of SOX9

  • In this study, we demonstrate that the canonical SOX-binding site within the human AMH proximal promoter can bind the transcription factor SOX9, a Sertoli cell factor closely associated with Sertoli cell differentiation and AMH expression [28].
  • These PIAS proteins were shown to interact directly with SOX9 in two-hybrid, co-immunoprecipitation, and electrophoretic mobility shift assays [29].
  • We show that SOX9 directly interacts with RUNX2 and represses its activity via their evolutionarily conserved high-mobility-group and runt domains [4].
  • The implications of the present results are discussed regarding (a) the apparent dual function of certain basic amino acid residues in the HMG domain of SRY in both DNA binding and in nuclear localization and (b) the possible control of SOX9 in early gonadal differentiation at the level of nuclear translocation [30].
  • Through in vitro and in vivo studies we have identified the heat shock protein HSP70 as an interacting partner for SOX9 in chondrocyte and testicular cell lines [31].

Regulatory relationships of SOX9


Other interactions of SOX9


Analytical, diagnostic and therapeutic context of SOX9


  1. Toward understanding SOX9 function in chondrocyte differentiation. Lefebvre, V., de Crombrugghe, B. Matrix Biol. (1998) [Pubmed]
  2. Testis determination in mammals: more questions than answers. Veitia, R.A., Salas-Cortés, L., Ottolenghi, C., Pailhoux, E., Cotinot, C., Fellous, M. Mol. Cell. Endocrinol. (2001) [Pubmed]
  3. Mutations in SOX9, the gene responsible for Campomelic dysplasia and autosomal sex reversal. Kwok, C., Weller, P.A., Guioli, S., Foster, J.W., Mansour, S., Zuffardi, O., Punnett, H.H., Dominguez-Steglich, M.A., Brook, J.D., Young, I.D. Am. J. Hum. Genet. (1995) [Pubmed]
  4. Dominance of SOX9 function over RUNX2 during skeletogenesis. Zhou, G., Zheng, Q., Engin, F., Munivez, E., Chen, Y., Sebald, E., Krakow, D., Lee, B. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  5. Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations. Meyer, J., Südbeck, P., Held, M., Wagner, T., Schmitz, M.L., Bricarelli, F.D., Eggermont, E., Friedrich, U., Haas, O.A., Kobelt, A., Leroy, J.G., Van Maldergem, L., Michel, E., Mitulla, B., Pfeiffer, R.A., Schinzel, A., Schmidt, H., Scherer, G. Hum. Mol. Genet. (1997) [Pubmed]
  6. Hypoxia promotes the differentiated human articular chondrocyte phenotype through SOX9-dependent and -independent pathways. Lafont, J.E., Talma, S., Hopfgarten, C., Murphy, C.L. J. Biol. Chem. (2008) [Pubmed]
  7. Ectopic SOX9 mediates extracellular matrix deposition characteristic of organ fibrosis. Hanley, K.P., Oakley, F., Sugden, S., Wilson, D.I., Mann, D.A., Hanley, N.A. J. Biol. Chem. (2008) [Pubmed]
  8. Upregulation of SOX9 in lung adenocarcinoma and its involvement in the regulation of cell growth and tumorigenicity. Jiang, S.S., Fang, W.T., Hou, Y.H., Huang, S.F., Yen, B.L., Chang, J.L., Li, S.M., Liu, H.P., Liu, Y.L., Huang, C.T., Li, Y.W., Jang, T.H., Chan, S.H., Yang, S.J., Hsiung, C.A., Wu, C.W., Wang, L.H., Chang, I.S. Clin. Cancer Res. (2010) [Pubmed]
  9. Timing of SOX9 downregulation and female sex determination in gonads of the sea turtle Lepidochelys olivacea. Torres-Maldonado, L., Moreno-Mendoza, N., Landa, A., Merchant-Larios, H. J. Exp. Zool. (2001) [Pubmed]
  10. Sox9 is required for cartilage formation. Bi, W., Deng, J.M., Zhang, Z., Behringer, R.R., de Crombrugghe, B. Nat. Genet. (1999) [Pubmed]
  11. SOX9 directly regulates the type-II collagen gene. Bell, D.M., Leung, K.K., Wheatley, S.C., Ng, L.J., Zhou, S., Ling, K.W., Sham, M.H., Koopman, P., Tam, P.P., Cheah, K.S. Nat. Genet. (1997) [Pubmed]
  12. Sex reversal by loss of the C-terminal transactivation domain of human SOX9. Südbeck, P., Schmitz, M.L., Baeuerle, P.A., Scherer, G. Nat. Genet. (1996) [Pubmed]
  13. Sox9 expression during gonadal development implies a conserved role for the gene in testis differentiation in mammals and birds. Morais da Silva, S., Hacker, A., Harley, V., Goodfellow, P., Swain, A., Lovell-Badge, R. Nat. Genet. (1996) [Pubmed]
  14. RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition. Afonja, O., Raaka, B.M., Huang, A., Das, S., Zhao, X., Helmer, E., Juste, D., Samuels, H.H. Oncogene (2002) [Pubmed]
  15. Simple assay method for endocrine disrupters by in vitro quail embryo culture: nonylphenol acts as a weak estrogen in quail embryos. Nishijima, K., Esaka, K., Ibuki, H., Ono, K., Miyake, K., Kamihira, M., Iijima, S. J. Biosci. Bioeng. (2003) [Pubmed]
  16. Effects of potent vitamin D3 analogs on clonal proliferation of human prostate cancer cell lines. de Vos, S., Holden, S., Heber, D., Elstner, E., Binderup, L., Uskokovic, M., Rude, B., Chen, D.L., Le, J., Cho, S.K., Koeffler, H.P. Prostate (1997) [Pubmed]
  17. The Sry-related gene Sox9 is expressed during chondrogenesis in mouse embryos. Wright, E., Hargrave, M.R., Christiansen, J., Cooper, L., Kun, J., Evans, T., Gangadharan, U., Greenfield, A., Koopman, P. Nat. Genet. (1995) [Pubmed]
  18. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Foster, J.W., Dominguez-Steglich, M.A., Guioli, S., Kowk, G., Weller, P.A., Stevanović, M., Weissenbach, J., Mansour, S., Young, I.D., Goodfellow, P.N. Nature (1994) [Pubmed]
  19. SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene. Lefebvre, V., Huang, W., Harley, V.R., Goodfellow, P.N., de Crombrugghe, B. Mol. Cell. Biol. (1997) [Pubmed]
  20. Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for campomelic dysplasia. Sock, E., Pagon, R.A., Keymolen, K., Lissens, W., Wegner, M., Scherer, G. Hum. Mol. Genet. (2003) [Pubmed]
  21. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Wagner, T., Wirth, J., Meyer, J., Zabel, B., Held, M., Zimmer, J., Pasantes, J., Bricarelli, F.D., Keutel, J., Hustert, E. Cell (1994) [Pubmed]
  22. SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. Blache, P., van de Wetering, M., Duluc, I., Domon, C., Berta, P., Freund, J.N., Clevers, H., Jay, P. J. Cell Biol. (2004) [Pubmed]
  23. Regulation of SOX9 mRNA in Human Articular Chondrocytes Involving p38 MAPK Activation and mRNA Stabilization. Tew, S.R., Hardingham, T.E. J. Biol. Chem. (2006) [Pubmed]
  24. Functional and structural studies of wild type SOX9 and mutations causing campomelic dysplasia. McDowall, S., Argentaro, A., Ranganathan, S., Weller, P., Mertin, S., Mansour, S., Tolmie, J., Harley, V. J. Biol. Chem. (1999) [Pubmed]
  25. Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation. Malki, S., Nef, S., Notarnicola, C., Thevenet, L., Gasca, S., Méjean, C., Berta, P., Poulat, F., Boizet-Bonhoure, B. EMBO J. (2005) [Pubmed]
  26. Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer. Huang, W., Zhou, X., Lefebvre, V., de Crombrugghe, B. Mol. Cell. Biol. (2000) [Pubmed]
  27. SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation. Passeron, T., Valencia, J.C., Bertolotto, C., Hoashi, T., Le Pape, E., Takahashi, K., Ballotti, R., Hearing, V.J. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  28. Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene. De Santa Barbara, P., Bonneaud, N., Boizet, B., Desclozeaux, M., Moniot, B., Sudbeck, P., Scherer, G., Poulat, F., Berta, P. Mol. Cell. Biol. (1998) [Pubmed]
  29. Interactions between PIAS proteins and SOX9 result in an increase in the cellular concentrations of SOX9. Hattori, T., Eberspaecher, H., Lu, J., Zhang, R., Nishida, T., Kahyo, T., Yasuda, H., de Crombrugghe, B. J. Biol. Chem. (2006) [Pubmed]
  30. Two independent nuclear localization signals are present in the DNA-binding high-mobility group domains of SRY and SOX9. Südbeck, P., Scherer, G. J. Biol. Chem. (1997) [Pubmed]
  31. Identification of an interaction between SOX9 and HSP70. Marshall, O.J., Harley, V.R. FEBS Lett. (2001) [Pubmed]
  32. Smad3 induces chondrogenesis through the activation of SOX9 via CREB-binding protein/p300 recruitment. Furumatsu, T., Tsuda, M., Taniguchi, N., Tajima, Y., Asahara, H. J. Biol. Chem. (2005) [Pubmed]
  33. Identification of cis and trans-acting transcriptional regulators in chondroinduced fibroblasts from the pre-phenotypic gene expression profile. Yates, K.E. Gene (2006) [Pubmed]
  34. SOX9-dependent and -independent transcriptional regulation of human cartilage link protein. Kou, I., Ikegawa, S. J. Biol. Chem. (2004) [Pubmed]
  35. SOX9 is up-regulated by the transient expression of SRY specifically in Sertoli cell precursors. Sekido, R., Bar, I., Narváez, V., Penny, G., Lovell-Badge, R. Dev. Biol. (2004) [Pubmed]
  36. SOX9 expression does not correlate with type II collagen expression in adult articular chondrocytes. Aigner, T., Gebhard, P.M., Schmid, E., Bau, B., Harley, V., Pöschl, E. Matrix Biol. (2003) [Pubmed]
  37. SRY-negative 46,XX male with normal genitals, complete masculinization and infertility. Rajender, S., Rajani, V., Gupta, N.J., Chakravarty, B., Singh, L., Thangaraj, K. Mol. Hum. Reprod. (2006) [Pubmed]
  38. SOX9 binds DNA, activates transcription, and coexpresses with type II collagen during chondrogenesis in the mouse. Ng, L.J., Wheatley, S., Muscat, G.E., Conway-Campbell, J., Bowles, J., Wright, E., Bell, D.M., Tam, P.P., Cheah, K.S., Koopman, P. Dev. Biol. (1997) [Pubmed]
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