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Gene Review

Sox9  -  SRY (sex determining region Y)-box 9

Mus musculus

Synonyms: 2010306G03Rik, AV220920, Sox-9, Transcription factor SOX-9, mKIAA4243
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Disease relevance of Sox9


High impact information on Sox9

  • Here, we show that Sox9 is sufficient to induce testis formation in mice, indicating that it can substitute for the sex-determining gene Sry [6].
  • Sox9 induces testis development in XX transgenic mice [6].
  • To analyze Sox9 function during sex determination, we ectopically expressed this gene in XX gonads [6].
  • During embryogenesis, wild-type XX fetal gonads downregulate Sox9 expression, whereas XY and XX Ods/+ fetal gonads upregulate and maintain its expression [7].
  • Sox9 binds to essential sequences in the Col2a1 and collagen alpha2(XI) gene (Col11a2) chondrocyte-specific enhancers and can activate these enhancers in non-chondrocytic cells [8].

Chemical compound and disease context of Sox9


Biological context of Sox9

  • Apoptotic domains within the developing limbs were expanded, suggesting that Sox9 suppresses apoptosis [10].
  • A new long form of Sox5 (L-Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene [11].
  • However, Sox9 expression is detected not only in chondrogenic tissue but also in nonchondrogenic tissues, suggesting the existence of a molecular partner(s) required for Sox9 to control chondrogenesis and chondrogenic gene expression [12].
  • We propose that Ods sex reversal is due to the Dct promoter element interacting with gonad-specific enhancer elements to produce the observed male pattern expression of Sox9 in the embryonic gonads [13].
  • These phenotypes associated also with the decreased expression of Sox9, Desert hedgehog, Hsd3beta, Platelet/endothelial cell adhesion molecule, and alpha-smooth muscle actin, which are markers of the Sertoli, Leydig, endothelial, and peritubular myoid cells of the developing testis [14].

Anatomical context of Sox9

  • We conclude that Sox9 is required during sequential steps of the chondrocyte differentiation pathway [10].
  • The Sox9 transcription factor determines glial fate choice in the developing spinal cord [15].
  • In agreement, compound loss of Sox9 and Sox10 led to a further decrease in oligodendrocyte progenitors [15].
  • Inactivation of Sox9 in limb buds before mesenchymal condensations resulted in a complete absence of both cartilage and bone, but markers for the different axes of limb development showed a normal pattern of expression [10].
  • Astrocyte numbers were also severely reduced in the absence of Sox9 and did not recover at later stages of spinal cord development [15].

Associations of Sox9 with chemical compounds


Physical interactions of Sox9


Co-localisations of Sox9

  • Expression of Col2a1 colocalized with expression of Sox9 in all chondroprogenitor cells [24].

Regulatory relationships of Sox9

  • These data indicate that activation of SOX9 in the gonad is sufficient to trigger all the downstream events needed for the development of a fully fertile male and provide evidence that Sox9 may down-regulate Wnt4 expression in the gonad [25].
  • Here, we show that during oligodendrocyte development, Sox8 is expressed after Sox9, but before Sox10 [26].
  • We demonstrate that in Ods, the Dct promoter is capable of acting over a distance of 1 Mb to induce inappropriate expression of Sox9 in the retinal pigmented epithelium of the eye, causing the observed microphthalmia [13].
  • No clear indication of Sry-induced enhancement of Sox9 expression was obtained in the present series of experiments [27].
  • Hypoxia increased nuclear accumulation of HIF-1alpha and activated the Sox9 promoter [1].

Other interactions of Sox9

  • Embryos, in which Sox9 was deleted after mesenchymal condensations, exhibited a severe generalized chondrodysplasia, similar to that in Sox5; Sox6 double-null mutant mice [10].
  • Loss of Sox8 did not impair oligodendrocyte specification by itself, but enhanced the Sox9-dependent defect [26].
  • Sox9, the human homolog of which is responsible for the skeletal malformation syndrome campomelic dysplasia, was mapped proximal to D11Mit128 [28].
  • Sox9 is sufficient for functional testis development producing fertile male mice in the absence of Sry [25].
  • Long-range activation of Sox9 in Odd Sex (Ods) mice [13].

Analytical, diagnostic and therapeutic context of Sox9


  1. Hypoxia induces chondrocyte-specific gene expression in mesenchymal cells in association with transcriptional activation of Sox9. Robins, J.C., Akeno, N., Mukherjee, A., Dalal, R.R., Aronow, B.J., Koopman, P., Clemens, T.L. Bone (2005) [Pubmed]
  2. L-Sox5, Sox6 and Sox9 control essential steps of the chondrocyte differentiation pathway. Lefebvre, V., Behringer, R.R., de Crombrugghe, B. Osteoarthr. Cartil. (2001) [Pubmed]
  3. Potent inhibition of the master chondrogenic factor Sox9 gene by interleukin-1 and tumor necrosis factor-alpha. Murakami, S., Lefebvre, V., de Crombrugghe, B. J. Biol. Chem. (2000) [Pubmed]
  4. Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Akiyama, H., Lyons, J.P., Mori-Akiyama, Y., Yang, X., Zhang, R., Zhang, Z., Deng, J.M., Taketo, M.M., Nakamura, T., Behringer, R.R., McCrea, P.D., de Crombrugghe, B. Genes Dev. (2004) [Pubmed]
  5. Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. Bi, W., Huang, W., Whitworth, D.J., Deng, J.M., Zhang, Z., Behringer, R.R., de Crombrugghe, B. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  6. Sox9 induces testis development in XX transgenic mice. Vidal, V.P., Chaboissier, M.C., de Rooij, D.G., Schedl, A. Nat. Genet. (2001) [Pubmed]
  7. A transgenic insertion upstream of sox9 is associated with dominant XX sex reversal in the mouse. Bishop, C.E., Whitworth, D.J., Qin, Y., Agoulnik, A.I., Agoulnik, I.U., Harrison, W.R., Behringer, R.R., Overbeek, P.A. Nat. Genet. (2000) [Pubmed]
  8. Sox9 is required for cartilage formation. Bi, W., Deng, J.M., Zhang, Z., Behringer, R.R., de Crombrugghe, B. Nat. Genet. (1999) [Pubmed]
  9. Thyroxine downregulates Sox9 and promotes chondrocyte hypertrophy. Okubo, Y., Reddi, A.H. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  10. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Akiyama, H., Chaboissier, M.C., Martin, J.F., Schedl, A., de Crombrugghe, B. Genes Dev. (2002) [Pubmed]
  11. A new long form of Sox5 (L-Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene. Lefebvre, V., Li, P., de Crombrugghe, B. EMBO J. (1998) [Pubmed]
  12. Transcriptional coactivator PGC-1alpha regulates chondrogenesis via association with Sox9. Kawakami, Y., Tsuda, M., Takahashi, S., Taniguchi, N., Esteban, C.R., Zemmyo, M., Furumatsu, T., Lotz, M., Belmonte, J.C., Asahara, H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  13. Long-range activation of Sox9 in Odd Sex (Ods) mice. Qin, Y., Kong, L.K., Poirier, C., Truong, C., Overbeek, P.A., Bishop, C.E. Hum. Mol. Genet. (2004) [Pubmed]
  14. Sprouty2 is involved in male sex organogenesis by controlling fibroblast growth factor 9-induced mesonephric cell migration to the developing testis. Chi, L., Itäranta, P., Zhang, S., Vainio, S. Endocrinology (2006) [Pubmed]
  15. The Sox9 transcription factor determines glial fate choice in the developing spinal cord. Stolt, C.C., Lommes, P., Sock, E., Chaboissier, M.C., Schedl, A., Wegner, M. Genes Dev. (2003) [Pubmed]
  16. Sertoli cell differentiation is induced both cell-autonomously and through prostaglandin signaling during mammalian sex determination. Wilhelm, D., Martinson, F., Bradford, S., Wilson, M.J., Combes, A.N., Beverdam, A., Bowles, J., Mizusaki, H., Koopman, P. Dev. Biol. (2005) [Pubmed]
  17. Dexamethasone enhances SOX9 expression in chondrocytes. Sekiya, I., Koopman, P., Tsuji, K., Mertin, S., Harley, V., Yamada, Y., Shinomiya, K., Nifuji, A., Noda, M. J. Endocrinol. (2001) [Pubmed]
  18. The chondrogenic transcription factor Sox9 is a target of signaling by the parathyroid hormone-related peptide in the growth plate of endochondral bones. Huang, W., Chung, U.I., Kronenberg, H.M., de Crombrugghe , B. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  19. SOX9 enhances aggrecan gene promoter/enhancer activity and is up-regulated by retinoic acid in a cartilage-derived cell line, TC6. Sekiya, I., Tsuji, K., Koopman, P., Watanabe, H., Yamada, Y., Shinomiya, K., Nifuji, A., Noda, M. J. Biol. Chem. (2000) [Pubmed]
  20. NF-kappaB mediates inhibition of mesenchymal cell differentiation through a posttranscriptional gene silencing mechanism. Sitcheran, R., Cogswell, P.C., Baldwin, A.S. Genes Dev. (2003) [Pubmed]
  21. A zinc finger transcription factor, alphaA-crystallin binding protein 1, is a negative regulator of the chondrocyte-specific enhancer of the alpha1(II) collagen gene. Tanaka, K., Matsumoto, Y., Nakatani, F., Iwamoto, Y., Yamada, Y. Mol. Cell. Biol. (2000) [Pubmed]
  22. Trans-activation of the mouse cartilage-derived retinoic acid-sensitive protein gene by Sox9. Xie, W.F., Zhang, X., Sakano, S., Lefebvre, V., Sandell, L.J. J. Bone Miner. Res. (1999) [Pubmed]
  23. Highly conserved proximal promoter element harbouring paired Sox9-binding sites contributes to the tissue- and developmental stage-specific activity of the matrilin-1 gene. Rentsendorj, O., Nagy, A., Sinkó, I., Daraba, A., Barta, E., Kiss, I. Biochem. J. (2005) [Pubmed]
  24. Parallel expression of Sox9 and Col2a1 in cells undergoing chondrogenesis. Zhao, Q., Eberspaecher, H., Lefebvre, V., De Crombrugghe, B. Dev. Dyn. (1997) [Pubmed]
  25. Sox9 is sufficient for functional testis development producing fertile male mice in the absence of Sry. Qin, Y., Bishop, C.E. Hum. Mol. Genet. (2005) [Pubmed]
  26. Impact of transcription factor Sox8 on oligodendrocyte specification in the mouse embryonic spinal cord. Stolt, C.C., Schmitt, S., Lommes, P., Sock, E., Wegner, M. Dev. Biol. (2005) [Pubmed]
  27. Wilms' tumor suppressor gene (WT1) as a target gene of SRY function in a mouse ES cell line transfected with SRY. Toyooka, Y., Tanaka, S.S., Hirota, O., Tanaka, S., Takagi, N., Yamanouchi, K., Tojo, H., Tachi, C. Int. J. Dev. Biol. (1998) [Pubmed]
  28. Rbt (Rabo torcido), a new mouse skeletal mutation involved in anteroposterior patterning of the axial skeleton, maps close to the Ts (tail-short) locus and distal to the Sox9 locus on chromosome 11. Hustert, E., Scherer, G., Olowson, M., Guénet, J.L., Balling, R. Mamm. Genome (1996) [Pubmed]
  29. The transcription factor Sox9 is involved in BMP-2 signaling. Zehentner, B.K., Dony, C., Burtscher, H. J. Bone Miner. Res. (1999) [Pubmed]
  30. 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]
  31. Sox8 is a specific marker for muscle satellite cells and inhibits myogenesis. Schmidt, K., Glaser, G., Wernig, A., Wegner, M., Rosorius, O. J. Biol. Chem. (2003) [Pubmed]
  32. Accelerated up-regulation of L-Sox5, Sox6, and Sox9 by BMP-2 gene transfer during murine fracture healing. Uusitalo, H., Hiltunen, A., Ahonen, M., Gao, T.J., Lefebvre, V., Harley, V., Kähäri, V.M., Vuorio, E. J. Bone Miner. Res. (2001) [Pubmed]
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