SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It acts during chondrocyte differentiation 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.[3] 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.[4] Next, Sox9 activates FGF9 and forms feedforward loops with FGF9[5] and PGD2.[4] 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.[5] The association of SOX-9 and Dax1 actually creates Sertoli cells, another vital process in male development.[6]
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.[7][8]
Role in sex reversal
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;[4] the same is true if Dax1 is not present.[6] 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.[9]
↑Tommerup N, Schempp W, Meinecke P, Pedersen S, Bolund L, Brandt C, Goodpasture C, Guldberg P, Held KR, Reinwein H, et al. (Sep 1993). "Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to 17q24.3-q25.1". Nat Genet. 4 (2): 170–4. doi:10.1038/ng0693-170. PMID8348155.
↑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 (March 2009). "Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence". Nat. Genet. 41 (3): 359–64. doi:10.1038/ng.329. PMID19234473.
↑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". J. Biol. Chem. 277 (52): 50668–75. doi:10.1074/jbc.M206544200. PMID12381733.
Further reading
Ninomiya S, Narahara K, Tsuji K, et al. (1995). "Acampomelic campomelic syndrome and sex reversal associated with de novo t(12;17) translocation". Am. J. Med. Genet. 56 (1): 31–4. doi:10.1002/ajmg.1320560109. PMID7747782.
Lefebvre V, de Crombrugghe B (1998). "Toward understanding SOX9 function in chondrocyte differentiation". Matrix Biol. 16 (9): 529–40. doi:10.1016/S0945-053X(98)90065-8. PMID9569122.
Harley VR (2002). "The molecular action of testis-determining factors SRY and SOX9". Novartis Found. Symp. 244: 57–66, discussion 66–7, 79–85, 253–7. doi:10.1002/0470868732.ch6. PMID11990798.
Foster JW, Dominguez-Steglich MA, Guioli S, et al. (1995). "Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene". Nature. 372 (6506): 525–30. doi:10.1038/372525a0. PMID7990924.
Wagner T, Wirth J, Meyer J, et al. (1995). "Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9". Cell. 79 (6): 1111–20. doi:10.1016/0092-8674(94)90041-8. PMID8001137.
Südbeck P, Schmitz ML, Baeuerle PA, Scherer G (1996). "Sex reversal by loss of the C-terminal transactivation domain of human SOX9". Nat. Genet. 13 (2): 230–2. doi:10.1038/ng0696-230. PMID8640233.
Cameron FJ, Hageman RM, Cooke-Yarborough C, et al. (1997). "A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal". Hum. Mol. Genet. 5 (10): 1625–30. doi:10.1093/hmg/5.10.1625. PMID8894698.
Meyer J, Südbeck P, Held M, et al. (1997). "Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations". Hum. Mol. Genet. 6 (1): 91–8. doi:10.1093/hmg/6.1.91. PMID9002675.
McDowall S, Argentaro A, Ranganathan S, et al. (1999). "Functional and structural studies of wild type SOX9 and mutations causing campomelic dysplasia". J. Biol. Chem. 274 (34): 24023–30. doi:10.1074/jbc.274.34.24023. PMID10446171.
Ninomiya S, Yokoyama Y, Teraoka M, et al. (2001). "A novel mutation (296 del G) of the SOX90 gene in a patient with campomelic syndrome and sex reversal". Clin. Genet. 58 (3): 224–7. doi:10.1034/j.1399-0004.2000.580310.x. PMID11076045.
Preiss S, Argentaro A, Clayton A, et al. (2001). "Compound effects of point mutations causing campomelic dysplasia/autosomal sex reversal upon SOX9 structure, nuclear transport, DNA binding, and transcriptional activation". J. Biol. Chem. 276 (30): 27864–72. doi:10.1074/jbc.M101278200. PMID11323423.