SOX9 explained

Transcription factor SOX-9 is a protein that in humans is encoded by the SOX9 gene.[1] [2]

Function

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[3] and, with steroidogenic factor 1, regulates transcription of the anti-Müllerian hormone (AMH) gene.[2]

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.[4] 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.[5] Next, SOX9 activates FGF9 and forms feedforward loops with FGF9[6] and PGD2.[5] 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.[6] The association of SOX-9 and Dax1 actually creates Sertoli cells, another vital process in male development.[7] 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.[8]

Sox9, also known as SRY-Box Transcription Factor 9, is an important gene is sex determination. The SOX family of genes are all transcription factors for the Y chromosomal sex-determining factor SRY. The SRY gene encodes the SOX transcription factor while it upregulates Sox9. Sox9 then activates Fgf9, Fibroblast growth factor 9, which is another integral transcription factor in the formation of the male gonads. Fgf9 up-regulates Sox9 in a positive feedforward cascade, this causes the differentiation of sertoli cells leading to the formation of the testis.[9]

SOX-9 is a target of the Notch signaling pathway, as well as the Hedgehog pathway,[10] 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.[11]

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.[12]

Clinical significance

Mutations lead to the skeletal malformation syndrome campomelic dysplasia, frequently with autosomal sex-reversal and cleft palate.[13]

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.[13] [14]

The SOX9 protein has been implicated in both initiation and progression of multiple solid tumors.[15] 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,[16] colorectal,[17] breast[18] and other cancers, and therefore promotes lethal metastasis.[19] Many of these oncogenic effects of SOX9 appear dose-dependent.[20] [16] [15]

SOX9 localization and dynamics

SOX9 is mostly localizatied 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.[21]

Role in Sexual Differentiation

SOX9 helps channel SRY activation in sexual differentiation. Mutations in SOX9 or any associated genes can cause a reversal of sex. If FGF9, which is activated by SOX9, is not present, a fetus with both X and Y chromosomes will become female.[5] the same is true if DAX1 is not present. The related phenomena can be caused by unusual activity of the SRY in XX male syndrome, usually when it's translocated onto the X-chromosome and its activity is only activated in some cells.[22] Mutation or deletion of SOX9 could cause an XY fetus to be female because SOX9 is a critical effector gene that works because of the SRY gene to differentiate Sertoli cells and drive testis formation in males.[9]

Interactions

SOX9 has been shown to interact with steroidogenic factor 1, MED12,[23] MAF,[24] SWI/SNF, MLL3 and MLL4.[25]

Knock out models

Loss of function mutations with Sox9 can lead to campomelic dysplasia(CD), due to mutations affecting protein functions and translocations that disrupt gene expression. There have been Sox9 knockout mice that have shown improved stroke recovery, especially when inhibiting inhibitors of axonal sprouting such as NOGO and chondroitin sulfate proteoglycans (CSPGs). Sox9 ablation leads to decreased levels of CSPG, which increases tissue sparing and improved post-stroke neurological recovery. These Sox9 knockout mice promote reparative axonal sprouting, neuroprotection and recovery after stroke.[26]

See also

Further reading

Notes and References

  1. Tommerup N, Schempp W, Meinecke P, Pedersen S, Bolund L, Brandt C, Goodpasture C, Guldberg P, Held KR, Reinwein H . Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to 17q24.3-q25.1 . Nature Genetics . 4 . 2 . 170–174 . June 1993 . 8348155 . 10.1038/ng0693-170 . 12263655 .
  2. Web site: Entrez Gene: SOX9 SRY (sex determining region Y)-box 9 (campomelic dysplasia, autosomal sex-reversal).
  3. Book: Kumar V, Abbas AK, Aster JC . Robbins and Cotran pathologic basis of disease . 9780808924500 . 1182 . Ninth . 2015 . Elsevier/Saunders .
  4. De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck P, Scherer G, Poulat F, Berta P . 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 . 6653–6665 . November 1998 . 9774680 . 109250 . 10.1128/mcb.18.11.6653 .
  5. Moniot B, Declosmenil F, Barrionuevo F, Scherer G, Aritake K, Malki S, Marzi L, Cohen-Solal A, Georg I, Klattig J, Englert C, Kim Y, Capel B, Eguchi N, Urade Y, Boizet-Bonhoure B, Poulat F . The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation . Development . 136 . 11 . 1813–1821 . June 2009 . 19429785 . 4075598 . 10.1242/dev.032631 .
  6. Kim Y, Kobayashi A, Sekido R, DiNapoli L, Brennan J, Chaboissier MC, Poulat F, Behringer RR, Lovell-Badge R, Capel B . Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination . PLOS Biology . 4 . 6 . e187 . June 2006 . 16700629 . 1463023 . 10.1371/journal.pbio.0040187 . free .
  7. Bouma GJ, Albrecht KH, Washburn LL, Recknagel AK, Churchill GA, Eicher EM . Gonadal sex reversal in mutant Dax1 XY mice: a failure to upregulate Sox9 in pre-Sertoli cells . Development . 132 . 13 . 3045–3054 . July 2005 . 15944188 . 10.1242/dev.01890 . free .
  8. Ambrozkiewicz MC, Schwark M, Kishimoto-Suga M, Borisova E, Hori K, Salazar-Lázaro A, Rusanova A, Altas B, Piepkorn L, Bessa P, Schaub T, Zhang X, Rabe T, Ripamonti S, Rosário M, Akiyama H, Jahn O, Kobayashi T, Hoshino M, Tarabykin V, Kawabe H . 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 . December 2018 . 30392800 . 10.1016/j.neuron.2018.10.008 . free .
  9. Gonen N, Quinn A, O'Neill HC, Koopman P, Lovell-Badge R . Normal Levels of Sox9 Expression in the Developing Mouse Testis Depend on the TES/TESCO Enhancer, but This Does Not Act Alone . PLOS Genetics . 13 . 1 . e1006520 . January 2017 . 28045957 . 5207396 . 10.1371/journal.pgen.1006520 . free .
  10. 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
  11. 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
  12. Ball HC, Ansari MY, Ahmad N, Novak K, Haqqi TM . 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 . November 2021 . 33043724 . 8404968 . 10.1080/03008207.2020.1828380 .
  13. Dixon MJ, Marazita ML, Beaty TH, Murray JC . Cleft lip and palate: understanding genetic and environmental influences . Nature Reviews. Genetics . 12 . 3 . 167–178 . March 2011 . 21331089 . 3086810 . 10.1038/nrg2933 .
  14. Benko S, Fantes JA, Amiel J, Kleinjan DJ, Thomas S, Ramsay J, Jamshidi N, Essafi A, Heaney S, Gordon CT, McBride D, Golzio C, Fisher M, Perry P, Abadie V, Ayuso C, Holder-Espinasse M, Kilpatrick N, Lees MM, Picard A, Temple IK, Thomas P, Vazquez MP, Vekemans M, Roest Crollius H, Hastie ND, Munnich A, Etchevers HC, Pelet A, Farlie PG, Fitzpatrick DR, Lyonnet S . Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence . Nature Genetics . 41 . 3 . 359–364 . March 2009 . 19234473 . 10.1038/ng.329 . 29933548 .
  15. Jo A, Denduluri S, Zhang B, Wang Z, Yin L, Yan Z, Kang R, Shi LL, Mok J, Lee MJ, Haydon RC . The versatile functions of Sox9 in development, stem cells, and human diseases . Genes & Diseases . 1 . 2 . 149–161 . December 2014 . 25685828 . 4326072 . 10.1016/j.gendis.2014.09.004 .
  16. 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 . Transient Sox9 Expression Facilitates Resistance to Androgen-Targeted Therapy in Prostate Cancer . Clinical Cancer Research . 26 . 7 . 1678–1689 . April 2020 . 31919137 . 10.1158/1078-0432.CCR-19-0098 . free .
  17. Prévostel C, Blache P . The dose-dependent effect of SOX9 and its incidence in colorectal cancer . European Journal of Cancer . 86 . 150–157 . November 2017 . 28988015 . 10.1016/j.ejca.2017.08.037 .
  18. Grimm D, Bauer J, Wise P, Krüger M, Simonsen U, Wehland M, Infanger M, Corydon TJ . The role of SOX family members in solid tumours and metastasis . Seminars in Cancer Biology . 67 . Pt 1 . 122–153 . December 2020 . 30914279 . 10.1016/j.semcancer.2019.03.004 . free . free . 21.11116/0000-0007-D3EE-F .
  19. Aguilar-Medina M, Avendaño-Félix M, Lizárraga-Verdugo E, Bermúdez M, Romero-Quintana JG, Ramos-Payan R, Ruíz-García E, López-Camarillo C . SOX9 Stem-Cell Factor: Clinical and Functional Relevance in Cancer . Journal of Oncology . 2019 . 6754040 . 2019 . 31057614 . 6463569 . 10.1155/2019/6754040 . free .
  20. Yang X, Liang R, Liu C, Liu JA, Cheung MP, Liu X, Man OY, Guan XY, Lung HL, Cheung M . SOX9 is a dose-dependent metastatic fate determinant in melanoma . Journal of Experimental & Clinical Cancer Research . 38 . 1 . 17 . January 2019 . 30642390 . 6330758 . 10.1186/s13046-018-0998-6 . free .
  21. Govindaraj K, Hendriks J, Lidke DS, Karperien M, Post JN . 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 . January 2019 . 30465885 . 10.1016/j.bbagrm.2018.11.001 . free .
  22. Margarit E, Coll MD, Oliva R, Gómez D, Soler A, Ballesta F . 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 . 25–28 . January 2000 . 10602113 . 10.1002/(SICI)1096-8628(20000103)90:1<25::AID-AJMG5>3.0.CO;2-5 .
  23. Zhou R, Bonneaud N, Yuan CX, de Santa Barbara P, Boizet B, Schomber T, Scherer G, Roeder RG, Poulat F, Berta P . SOX9 interacts with a component of the human thyroid hormone receptor-associated protein complex . Nucleic Acids Research . 30 . 14 . 3245–3252 . July 2002 . 12136106 . 135763 . 10.1093/nar/gkf443 .
  24. Huang W, Lu N, Eberspaecher H, De Crombrugghe B . A new long form of c-Maf cooperates with Sox9 to activate the type II collagen gene . The Journal of Biological Chemistry . 277 . 52 . 50668–50675 . December 2002 . 12381733 . 10.1074/jbc.M206544200 . free .
  25. Yang Y, Gomez N, Infarinato N, Adam RC, Sribour M, Baek I, Laurin M, Fuchs E . The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates . Nature Cell Biology . 25 . 8 . 1185–1195 . August 2023 . 37488435 . 10415178 . 10.1038/s41556-023-01184-y . free .
  26. Xu X, Bass B, McKillop WM, Mailloux J, Liu T, Geremia NM, Hryciw T, Brown A . Sox9 knockout mice have improved recovery following stroke . Experimental Neurology . 303 . 59–71 . May 2018 . 29425963 . 10.1016/j.expneurol.2018.02.001 .

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