Transcription factor SOX-9 is a protein that in humans is encoded by the SOX9 gene.[5][6]

Available structures
PDBOrtholog search: PDBe RCSB
AliasesSOX9, CMD1, CMPD1, SRA1, SRXX2, SRXY10, SRY-box 9, SRY-box transcription factor 9
External IDsOMIM: 608160 MGI: 98371 HomoloGene: 294 GeneCards: SOX9
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 17: 72.12 – 72.13 MbChr 11: 112.67 – 112.68 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Function edit

SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It is expressed by proliferating but not hypertrophic chondrocytes that is essential for differentiation of precursor cells into chondrocytes[7] and, with steroidogenic factor 1, regulates transcription of the anti-Müllerian hormone (AMH) gene.[6]

SOX-9 also plays a pivotal role in male sexual development; by working with Sf1, SOX-9 can produce AMH in Sertoli cells to inhibit the creation of a female reproductive system.[8] It also interacts with a few other genes to promote the development of male sexual organs. The process starts when the transcription factor testis determining factor (encoded by the sex-determining region SRY of the Y chromosome) activates SOX-9 activity by binding to an enhancer sequence upstream of the gene.[9] Next, Sox9 activates FGF9 and forms feedforward loops with FGF9[10] and PGD2.[9] These loops are important for producing SOX-9; without these loops, SOX-9 would run out and the development of a female would almost certainly ensue. Activation of FGF9 by SOX-9 starts vital processes in male development, such as the creation of testis cords and the multiplication of Sertoli cells.[10] The association of SOX-9 and Dax1 actually creates Sertoli cells, another vital process in male development.[11] In the brain development, its murine ortholog Sox-9 induces the expression of Wwp1, Wwp2, and miR-140 to regulate cortical plate entry of newly born nerve cells, and regulate axon branching and axon formation in cortical neurons.[12]

SOX-9 is a target of the Notch signaling pathway, as well as the Hedgehog pathway,[13] and plays a role in the regulation of neural stem cell fate. In vivo and in vitro studies show that SOX-9 negatively regulates neurogenesis and positively regulates gliogenesis and stem cell survival.[14]

In adult articular chondrocytes, siRNA-mediated knockdown of SOX-9 or RTL3 results in the downregulation of the other and reduced type II collagen (COL2A1) mRNA and protein expression.[15]

Clinical significance edit

Mutations lead to the skeletal malformation syndrome campomelic dysplasia, frequently with autosomal sex-reversal[6] and cleft palate.[16]

SOX9 sits in a gene desert on 17q24 in humans. Deletions, disruptions by translocation breakpoints and a single point mutation of highly conserved non-coding elements located > 1 Mb from the transcription unit on either side of SOX9 have been associated with Pierre Robin Sequence, often with a cleft palate.[16][17]

The Sox9 protein has been implicated in both initiation and progression of multiple solid tumors.[18] Its role as a master regulator of morphogenesis during human development makes it an ideal candidate for perturbation in malignant tissues. Specifically, Sox9 appears to induce invasiveness and therapy-resistance in prostate,[19] colorectal,[20] breast[21] and other cancers, and therefore promotes lethal metastasis.[22] Many of these oncogenic effects of Sox9 appear dose dependent.[23][19][18]

SOX9 localisation and dynamics edit

SOX9 is mostly localised in the nucleus and it is highly mobile. Studies in chondrocyte cell line has revealed nearly 50% of SOX9 is bound to DNA and it is directly regulated by external factors. Its half-time of residence on DNA is ~14 seconds.[24]

Role in sex reversal edit

Mutations in Sox9 or any associated genes can cause reversal of sex and hermaphroditism (or intersexuality in humans). If Fgf9, which is activated by Sox9, is not present, a fetus with both X and Y chromosomes can develop female gonads;[9] the same is true if Dax1 is not present.[11] The related phenomena of hermaphroditism can be caused by unusual activity of the SRY, usually when it's translocated onto the X-chromosome and its activity is only activated in some cells.[25]

Interactions edit

SOX9 has been shown to interact with steroidogenic factor 1,[8] MED12,[26] MAF,[27] SWI/SNF, MLL3 and MLL4.[28]

See also edit

Further reading edit

References edit

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000125398 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000567 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Tommerup N, Schempp W, Meinecke P, Pedersen S, Bolund L, Brandt C, et al. (June 1993). "Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to 17q24.3-q25.1". Nature Genetics. 4 (2): 170–4. doi:10.1038/ng0693-170. PMID 8348155. S2CID 12263655.
  6. ^ a b c "Entrez Gene: SOX9 SRY (sex determining region Y)-box 9 (campomelic dysplasia, autosomal sex-reversal)".
  7. ^ Kumar V, Abbas AK, Aster JC (2015). Robbins and Cotran pathologic basis of disease (Ninth ed.). Elsevier/Saunders. p. 1182. ISBN 9780808924500.
  8. ^ a b De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck P, et al. (November 1998). "Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene". Molecular and Cellular Biology. 18 (11): 6653–65. doi:10.1128/mcb.18.11.6653. PMC 109250. PMID 9774680.
  9. ^ a b c Moniot B, Declosmenil F, Barrionuevo F, Scherer G, Aritake K, Malki S, et al. (June 2009). "The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation". Development. 136 (11): 1813–21. doi:10.1242/dev.032631. PMC 4075598. PMID 19429785.
  10. ^ a b Kim Y, Kobayashi A, Sekido R, DiNapoli L, Brennan J, Chaboissier MC, et al. (June 2006). "Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination". PLOS Biology. 4 (6): e187. doi:10.1371/journal.pbio.0040187. PMC 1463023. PMID 16700629.
  11. ^ a b Bouma GJ, Albrecht KH, Washburn LL, Recknagel AK, Churchill GA, Eicher EM (July 2005). "Gonadal sex reversal in mutant Dax1 XY mice: a failure to upregulate Sox9 in pre-Sertoli cells". Development. 132 (13): 3045–54. doi:10.1242/dev.01890. PMID 15944188.
  12. ^ Ambrozkiewicz MC, Schwark M, Kishimoto-Suga M, Borisova E, Hori K, Salazar-Lázaro A, et al. (December 2018). "Polarity Acquisition in Cortical Neurons Is Driven by Synergistic Action of Sox9-Regulated Wwp1 and Wwp2 E3 Ubiquitin Ligases and Intronic miR-140". Neuron. 100 (5): 1097–1115.e15. doi:10.1016/j.neuron.2018.10.008. PMID 30392800.
  13. ^ Place E, Manning E, Kim DW, Kinjo A, Nakamura G and Ohyama K (2022) SHH and Notch regulate SOX9+ progenitors to govern arcuate POMC neurogenesis. Front. Neurosci. 16:855288. doi: 10.3389/fnins.2022.855288
  14. ^ Vogel, Julia K.; Wegner, Michael PhD,*. Sox9 in the developing central nervous system: a jack of all trades?. Neural Regeneration Research 16(4):p 676-677, April 2021. | DOI: 10.4103/1673-5374.295327
  15. ^ Ball HC, Ansari MY, Ahmad N, Novak K, Haqqi TM (November 2021). "A retrotransposon gag-like-3 gene RTL3 and SOX-9 co-regulate the expression of COL2A1 in chondrocytes". Connective Tissue Research. 62 (6): 615–628. doi:10.1080/03008207.2020.1828380. ISSN 1607-8438. PMC 8404968. PMID 33043724.
  16. ^ a b Dixon MJ, Marazita ML, Beaty TH, Murray JC (March 2011). "Cleft lip and palate: understanding genetic and environmental influences". Nature Reviews. Genetics. 12 (3): 167–78. doi:10.1038/nrg2933. PMC 3086810. PMID 21331089.
  17. ^ Benko S, Fantes JA, Amiel J, Kleinjan DJ, Thomas S, Ramsay J, et al. (March 2009). "Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence". Nature Genetics. 41 (3): 359–64. doi:10.1038/ng.329. PMID 19234473. S2CID 29933548.
  18. ^ a b Jo A, Denduluri S, Zhang B, Wang Z, Yin L, Yan Z, Kang R, Shi LL, Mok J, Lee MJ, Haydon RC (December 2014). "The versatile functions of Sox9 in development, stem cells, and human diseases". Genes & Diseases. 1 (2): 149–161. doi:10.1016/j.gendis.2014.09.004. PMC 4326072. PMID 25685828.
  19. ^ a b Nouri M, Massah S, Caradec J, Lubik AA, Li N, Truong S, Lee AR, Fazli L, Ramnarine VR, Lovnicki JM, Moore J, Wang M, Foo J, Gleave ME, Hollier BG, Nelson C, Collins C, Dong X, Buttyan R (9 January 2020). "Transient Sox9 Expression Facilitates Resistance to Androgen-Targeted Therapy in Prostate Cancer". Clinical Cancer Research. 26 (7): 1678–1689. doi:10.1158/1078-0432.CCR-19-0098. PMID 31919137.
  20. ^ Prévostel C, Blache P (November 2017). "The dose-dependent effect of SOX9 and its incidence in colorectal cancer". European Journal of Cancer. 86: 150–157. doi:10.1016/j.ejca.2017.08.037. PMID 28988015.
  21. ^ Grimm D, Bauer J, Wise P, Krüger M, Simonsen U, Wehland M, Infanger M, Corydon TJ (23 March 2019). "The role of SOX family members in solid tumours and metastasis". Seminars in Cancer Biology. 67 (Pt 1): 122–153. doi:10.1016/j.semcancer.2019.03.004. hdl:21.11116/0000-0007-D3EE-F. PMID 30914279.
  22. ^ Aguilar-Medina M, Avendaño-Félix M, Lizárraga-Verdugo E, Bermúdez M, Romero-Quintana JG, Ramos-Payan R, Ruíz-García E, López-Camarillo C (2019). "SOX9 Stem-Cell Factor: Clinical and Functional Relevance in Cancer". Journal of Oncology. 2019: 6754040. doi:10.1155/2019/6754040. PMC 6463569. PMID 31057614.
  23. ^ Yang X, Liang R, Liu C, Liu JA, Cheung M, Liu X, Man OY, Guan XY, Lung HL, Cheung M (14 January 2019). "SOX9 is a dose-dependent metastatic fate determinant in melanoma". Journal of Experimental & Clinical Cancer Research. 38 (1): 17. doi:10.1186/s13046-018-0998-6. PMC 6330758. PMID 30642390.
  24. ^ Govindaraj K, Hendriks J, Lidke DS, Karperien M, Post JN (January 2019). "Changes in Fluorescence Recovery After Photobleaching (FRAP) as an indicator of SOX9 transcription factor activity". Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 1862 (1): 107–117. doi:10.1016/j.bbagrm.2018.11.001. PMID 30465885.
  25. ^ Margarit E, Coll MD, Oliva R, Gómez D, Soler A, Ballesta F (January 2000). "SRY gene transferred to the long arm of the X chromosome in a Y-positive XX true hermaphrodite". American Journal of Medical Genetics. 90 (1): 25–8. doi:10.1002/(SICI)1096-8628(20000103)90:1<25::AID-AJMG5>3.0.CO;2-5. PMID 10602113.
  26. ^ Zhou R, Bonneaud N, Yuan CX, de Santa Barbara P, Boizet B, Schomber T, et al. (July 2002). "SOX9 interacts with a component of the human thyroid hormone receptor-associated protein complex". Nucleic Acids Research. 30 (14): 3245–52. doi:10.1093/nar/gkf443. PMC 135763. PMID 12136106.
  27. ^ Huang W, Lu N, Eberspaecher H, De Crombrugghe B (December 2002). "A new long form of c-Maf cooperates with Sox9 to activate the type II collagen gene". The Journal of Biological Chemistry. 277 (52): 50668–75. doi:10.1074/jbc.M206544200. PMID 12381733.
  28. ^ Yang Y, Gomez N, Infarinato N, Adam RC, Sribour M, Baek I, Laurin M, Fuchs E (2023-07-24). "The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates". Nature Cell Biology. 25 (8): 1185–1195. doi:10.1038/s41556-023-01184-y. ISSN 1476-4679. PMC 10415178. PMID 37488435.

External links edit

This article incorporates text from the United States National Library of Medicine, which is in the public domain.