SOX9: Difference between revisions

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{{Infobox_gene}}
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'''Transcription factor SOX-9''' is a [[protein]] that in humans is encoded by the ''SOX9'' [[gene]].<ref name="pmid8348155">{{cite journal  |vauthors=Tommerup N, Schempp W, Meinecke P, Pedersen S, Bolund L, Brandt C, Goodpasture C, Guldberg P, Held KR, Reinwein H, etal | title = Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to 17q24.3-q25.1 | journal = Nat Genet | volume = 4 | issue = 2 | pages = 170–4 |date=Sep 1993 | pmid = 8348155 | pmc =  | doi = 10.1038/ng0693-170 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SOX9 SRY (sex determining region Y)-box 9 (campomelic dysplasia, autosomal sex-reversal)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6662| accessdate = }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = SRY (sex determining region Y)-box 9 (campomelic dysplasia, autosomal sex-reversal)
| HGNCid = 11204
| Symbol = SOX9
| AltSymbols =; CMPD1; CMD1; SRA1
| OMIM = 608160
| ECnumber = 
| Homologene = 294
| MGIid = 98371
| GeneAtlas_image1 = PBB_GE_SOX9_202936_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_SOX9_202935_s_at_tn.png
| Function = {{GNF_GO|id=GO:0003677 |text = DNA binding}} {{GNF_GO|id=GO:0003704 |text = specific RNA polymerase II transcription factor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0016563 |text = transcription activator activity}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0001501 |text = skeletal development}} {{GNF_GO|id=GO:0001502 |text = cartilage condensation}} {{GNF_GO|id=GO:0001708 |text = cell fate specification}} {{GNF_GO|id=GO:0001837 |text = epithelial to mesenchymal transition}} {{GNF_GO|id=GO:0001942 |text = hair follicle development}} {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0007507 |text = heart development}} {{GNF_GO|id=GO:0008584 |text = male gonad development}} {{GNF_GO|id=GO:0014032 |text = neural crest cell development}} {{GNF_GO|id=GO:0019100 |text = male germ-line sex determination}} {{GNF_GO|id=GO:0042127 |text = regulation of cell proliferation}} {{GNF_GO|id=GO:0042981 |text = regulation of apoptosis}} {{GNF_GO|id=GO:0045892 |text = negative regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0045944 |text = positive regulation of transcription from RNA polymerase II promoter}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 6662
    | Hs_Ensembl = ENSG00000125398
    | Hs_RefseqProtein = NP_000337
    | Hs_RefseqmRNA = NM_000346
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 17
    | Hs_GenLoc_start = 67628756
    | Hs_GenLoc_end = 67634147
    | Hs_Uniprot = P48436
    | Mm_EntrezGene = 20682
    | Mm_Ensembl = ENSMUSG00000000567
    | Mm_RefseqmRNA = NM_011448
    | Mm_RefseqProtein = NP_035578
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 112598314
    | Mm_GenLoc_end = 112603839
    | Mm_Uniprot = Q571J2
  }}
}}
'''SRY (sex determining region Y)-box 9 ([[camptomelic dysplasia|campomelic dysplasia]], autosomal sex-reversal)''', also known as '''SOX9''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: SOX9 SRY (sex determining region Y)-box 9 (campomelic dysplasia, autosomal sex-reversal)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6662| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
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 ([[Anti-Müllerian hormone|AMH]]) gene.<ref name="entrez"/>
{{PBB_Summary
 
| section_title =
SOX-9 also plays a pivotal role in male sexual development; by working with Sf1, SOX-9 can produce AMH in [[Sertoli cell]]s to inhibit the creation of a female reproductive system.<ref name="pmid9774680">{{cite journal | vauthors = De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck P, Scherer G, Poulat F, Berta P | title = Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene | journal = Mol. Cell. Biol. | volume = 18 | issue = 11 | pages = 6653–65 |date=November 1998 | pmid = 9774680 | pmc = 109250 | doi =  10.1128/mcb.18.11.6653}}</ref> 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 (genetics)|enhancer]] sequence [[Upstream and downstream (DNA)|upstream]] of the gene.<ref name="Moniot">{{cite journal | vauthors = 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 | title = The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation | journal = Development | volume = 136 | issue = 11 | pages = 1813–21 |date=June 2009 | pmid = 19429785 | doi = 10.1242/dev.032631 | url = }}</ref> Next, Sox9 activates [[FGF9]] and forms feedforward loops with FGF9<ref name="pmid16700629">{{cite journal | vauthors = Kim Y, Kobayashi A, Sekido R, DiNapoli L, Brennan J, Chaboissier MC, Poulat F, Behringer RR, Lovell-Badge R, Capel B | title = Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination | journal = PLoS Biol. | volume = 4 | issue = 6 | pages = e187 |date=June 2006 | pmid = 16700629 | pmc = 1463023 | doi = 10.1371/journal.pbio.0040187  }}</ref> and [[PGD2]].<ref name="Moniot"/>  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 cell]]s.<ref name="pmid16700629"/> The association of SOX-9 and [[Dax1]] actually creates Sertoli cells, another vital process in male development.<ref name="pmid15944188">{{cite journal | vauthors = Bouma GJ, Albrecht KH, Washburn LL, Recknagel AK, Churchill GA, Eicher EM | title = Gonadal sex reversal in mutant Dax1 XY mice: a failure to upregulate Sox9 in pre-Sertoli cells | journal = Development | volume = 132 | issue = 13 | pages = 3045–54 |date=July 2005 | pmid = 15944188 | doi = 10.1242/dev.01890 }}</ref>
| summary_text = The protein encoded by this gene 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-Muellerian hormone (AMH) gene. Deficiencies lead to the skeletal malformation syndrome campomelic dysplasia, frequently with sex reversal.<ref name="entrez">{{cite web | title = Entrez Gene: SOX9 SRY (sex determining region Y)-box 9 (campomelic dysplasia, autosomal sex-reversal)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6662| accessdate = }}</ref>
 
}}
== Clinical significance ==
 
Mutations lead to the skeletal malformation syndrome [[campomelic dysplasia]], frequently with autosomal sex-reversal<ref name="entrez" /> and [[cleft palate]].<ref name="Dixon_2011">{{cite journal | vauthors = Dixon MJ, Marazita ML, Beaty TH, Murray JC | title = Cleft lip and palate: understanding genetic and environmental influences | journal = Nat. Rev. Genet. | volume = 12 | issue = 3 | pages = 167–78 |date=March 2011 | pmid = 21331089 | pmc = 3086810 | doi = 10.1038/nrg2933  }}</ref>
 
SOX9 sits in a gene desert on 17q24 in humans. Deletions, disruptions by [[chromosomal translocation|translocation]] breakpoints and a single point mutation of highly conserved non-coding elements located > 1 [[Base pair#Length measurements|Mb]] from the transcription unit on either side of SOX9 have been associated with [[Pierre Robin syndrome|Pierre Robin Sequence]], often with a [[cleft palate]].<ref name="Dixon_2011"/><ref name="pmid19234473">{{cite journal | vauthors = 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 | title = Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence | journal = Nat. Genet. | volume = 41 | issue = 3 | pages = 359–64 |date=March 2009 | pmid = 19234473 | doi = 10.1038/ng.329 }}</ref>
 
===Role in sex reversal===
 
[[Mutation]]s in Sox9 or any associated genes can cause reversal of sex and [[hermaphroditism]] (or [[intersex|intersexuality]] in humans). If Fgf9, which is activated by Sox9, is not present, a [[fetus]] with both X and Y [[chromosome]]s can develop female gonads;<ref name="Moniot"/> the same is true if [[Dax1]] is not present.<ref name="pmid15944188" /> The related phenomena of hermaphroditism/intersexuality 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.<ref name="pmid10602113">{{cite journal | vauthors = Margarit E, Coll MD, Oliva R, Gómez D, Soler A, Ballesta F | title = SRY gene transferred to the long arm of the X chromosome in a Y-positive XX true hermaphrodite | journal = Am. J. Med. Genet. | volume = 90 | issue = 1 | pages = 25–8 |date=January 2000 | pmid = 10602113 | doi = 10.1002/(SICI)1096-8628(20000103)90:1<25::AID-AJMG5>3.0.CO;2-5}}</ref>
 
== Interactions ==
 
SOX9 has been shown to [[Protein-protein interaction|interact]] with [[Steroidogenic factor 1]],<ref name="pmid9774680" /> [[MED12]]<ref name="pmid12136106">{{cite journal | vauthors = Zhou R, Bonneaud N, Yuan CX, de Santa Barbara P, Boizet B, Schomber T, Scherer G, Roeder RG, Poulat F, Berta P, Tibor S | title = SOX9 interacts with a component of the human thyroid hormone receptor-associated protein complex | journal = Nucleic Acids Res. | volume = 30 | issue = 14 | pages = 3245–52 |date=July 2002 | pmid = 12136106 | pmc = 135763 | doi = 10.1093/nar/gkf443 | url = | issn = }}</ref> and [[MAF (gene)|MAF]].<ref name="pmid12381733">{{cite journal | vauthors = Huang W, Lu N, Eberspaecher H, De Crombrugghe B | title = A new long form of c-Maf cooperates with Sox9 to activate the type II collagen gene | journal = J. Biol. Chem. | volume = 277 | issue = 52 | pages = 50668–75 |date=December 2002 | pmid = 12381733 | doi = 10.1074/jbc.M206544200 | url = | issn = }}</ref>


==See also==
==See also==
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==References==
==References==
{{reflist|2}}
{{reflist}}


==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
*{{cite journal   |vauthors=Ninomiya S, Narahara K, Tsuji K, etal |title=Acampomelic campomelic syndrome and sex reversal associated with de novo t(12;17) translocation. |journal=Am. J. Med. Genet. |volume=56 |issue= 1 |pages= 31–4 |year= 1995 |pmid= 7747782 |doi= 10.1002/ajmg.1320560109 }}
| citations =
*{{cite journal  | vauthors=Lefebvre V, de Crombrugghe B |title=Toward understanding SOX9 function in chondrocyte differentiation. |journal=Matrix Biol. |volume=16 |issue= 9 |pages= 529–40 |year= 1998 |pmid= 9569122 |doi=10.1016/S0945-053X(98)90065-8 }}
*{{cite journal | author=Ninomiya S, Narahara K, Tsuji K, ''et al.'' |title=Acampomelic campomelic syndrome and sex reversal associated with de novo t(12;17) translocation. |journal=Am. J. Med. Genet. |volume=56 |issue= 1 |pages= 31-4 |year= 1995 |pmid= 7747782 |doi= 10.1002/ajmg.1320560109 }}
*{{cite journal  | author=Harley VR |title=The molecular action of testis-determining factors SRY and SOX9. |journal=Novartis Found. Symp. |volume=244 |issue=  |pages= 57–66; discussion 66–7, 79–85, 253–7 |year= 2002 |pmid= 11990798 |doi=10.1002/0470868732.ch6 }}
*{{cite journal  | author=Lefebvre V, de Crombrugghe B |title=Toward understanding SOX9 function in chondrocyte differentiation. |journal=Matrix Biol. |volume=16 |issue= 9 |pages= 529-40 |year= 1998 |pmid= 9569122 |doi=  }}
*{{cite journal   |vauthors=Kwok C, Weller PA, Guioli S, etal |title=Mutations in SOX9, the gene responsible for Campomelic dysplasia and autosomal sex reversal. |journal=Am. J. Hum. Genet. |volume=57 |issue= 5 |pages= 1028–36 |year= 1995 |pmid= 7485151 |doi= | pmc=1801368 }}
*{{cite journal  | author=Harley VR |title=The molecular action of testis-determining factors SRY and SOX9. |journal=Novartis Found. Symp. |volume=244 |issue=  |pages= 57-66; discussion 66-7, 79-85, 253-7 |year= 2002 |pmid= 11990798 |doi=  }}
*{{cite journal   |vauthors=Foster JW, Dominguez-Steglich MA, Guioli S, etal |title=Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. |journal=Nature |volume=372 |issue= 6506 |pages= 525–30 |year= 1995 |pmid= 7990924 |doi= 10.1038/372525a0 }}
*{{cite journal | author=Kwok C, Weller PA, Guioli S, ''et al.'' |title=Mutations in SOX9, the gene responsible for Campomelic dysplasia and autosomal sex reversal. |journal=Am. J. Hum. Genet. |volume=57 |issue= 5 |pages= 1028-36 |year= 1995 |pmid= 7485151 |doi=  }}
*{{cite journal   |vauthors=Wagner T, Wirth J, Meyer J, etal |title=Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. |journal=Cell |volume=79 |issue= 6 |pages= 1111–20 |year= 1995 |pmid= 8001137 |doi=10.1016/0092-8674(94)90041-8 }}
*{{cite journal | author=Foster JW, Dominguez-Steglich MA, Guioli S, ''et al.'' |title=Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. |journal=Nature |volume=372 |issue= 6506 |pages= 525-30 |year= 1995 |pmid= 7990924 |doi= 10.1038/372525a0 }}
*{{cite journal  | vauthors=Südbeck P, Schmitz ML, Baeuerle PA, Scherer G |title=Sex reversal by loss of the C-terminal transactivation domain of human SOX9. |journal=Nat. Genet. |volume=13 |issue= 2 |pages= 230–2 |year= 1996 |pmid= 8640233 |doi= 10.1038/ng0696-230 }}
*{{cite journal | author=Wagner T, Wirth J, Meyer J, ''et al.'' |title=Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. |journal=Cell |volume=79 |issue= 6 |pages= 1111-20 |year= 1995 |pmid= 8001137 |doi=  }}
*{{cite journal   |vauthors=Cameron FJ, Hageman RM, Cooke-Yarborough C, etal |title=A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal. |journal=Hum. Mol. Genet. |volume=5 |issue= 10 |pages= 1625–30 |year= 1997 |pmid= 8894698 |doi=10.1093/hmg/5.10.1625  }}
*{{cite journal  | author=Tommerup N, Schempp W, Meinecke P, ''et al.'' |title=Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to 17q24.3-q25.1. |journal=Nat. Genet. |volume=4 |issue= 2 |pages= 170-4 |year= 1993 |pmid= 8348155 |doi= 10.1038/ng0693-170 }}
*{{cite journal   |vauthors=Meyer J, Südbeck P, Held M, etal |title=Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations. |journal=Hum. Mol. Genet. |volume=6 |issue= 1 |pages= 91–8 |year= 1997 |pmid= 9002675 |doi=10.1093/hmg/6.1.91 }}
*{{cite journal | author=Südbeck P, Schmitz ML, Baeuerle PA, Scherer G |title=Sex reversal by loss of the C-terminal transactivation domain of human SOX9. |journal=Nat. Genet. |volume=13 |issue= 2 |pages= 230-2 |year= 1996 |pmid= 8640233 |doi= 10.1038/ng0696-230 }}
*{{cite journal  | vauthors=Cameron FJ, Sinclair AH |title=Mutations in SRY and SOX9: testis-determining genes. |journal=Hum. Mutat. |volume=9 |issue= 5 |pages= 388–95 |year= 1997 |pmid= 9143916 |doi= 10.1002/(SICI)1098-1004(1997)9:5<388::AID-HUMU2>3.0.CO;2-0 }}
*{{cite journal | author=Cameron FJ, Hageman RM, Cooke-Yarborough C, ''et al.'' |title=A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal. |journal=Hum. Mol. Genet. |volume=5 |issue= 10 |pages= 1625-30 |year= 1997 |pmid= 8894698 |doi=  }}
*{{cite journal   |vauthors=Wunderle VM, Critcher R, Hastie N, etal |title=Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue= 18 |pages= 10649–54 |year= 1998 |pmid= 9724758 |doi=10.1073/pnas.95.18.10649  | pmc=27949  }}
*{{cite journal  | author=Meyer J, Südbeck P, Held M, ''et al.'' |title=Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations. |journal=Hum. Mol. Genet. |volume=6 |issue= 1 |pages= 91-8 |year= 1997 |pmid= 9002675 |doi= }}
*{{cite journal   |vauthors=De Santa Barbara P, Bonneaud N, Boizet B, etal |title=Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene. |journal=Mol. Cell. Biol. |volume=18 |issue= 11 |pages= 6653–65 |year= 1998 |pmid= 9774680 |doi= 10.1128/mcb.18.11.6653| pmc=109250 }}
*{{cite journal  | author=Cameron FJ, Sinclair AH |title=Mutations in SRY and SOX9: testis-determining genes. |journal=Hum. Mutat. |volume=9 |issue= 5 |pages= 388-95 |year= 1997 |pmid= 9143916 |doi= 10.1002/(SICI)1098-1004(1997)9:5<388::AID-HUMU2>3.0.CO;2-0 }}
*{{cite journal   |vauthors=McDowall S, Argentaro A, Ranganathan S, etal |title=Functional and structural studies of wild type SOX9 and mutations causing campomelic dysplasia. |journal=J. Biol. Chem. |volume=274 |issue= 34 |pages= 24023–30 |year= 1999 |pmid= 10446171 |doi=10.1074/jbc.274.34.24023 }}
*{{cite journal | author=Wunderle VM, Critcher R, Hastie N, ''et al.'' |title=Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue= 18 |pages= 10649-54 |year= 1998 |pmid= 9724758 |doi=  }}
*{{cite journal  | vauthors=Huang W, Zhou X, Lefebvre V, de Crombrugghe B |title=Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer. |journal=Mol. Cell. Biol. |volume=20 |issue= 11 |pages= 4149–58 |year= 2000 |pmid= 10805756 |doi=10.1128/MCB.20.11.4149-4158.2000  | pmc=85784 }}
*{{cite journal | author=De Santa Barbara P, Bonneaud N, Boizet B, ''et al.'' |title=Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene. |journal=Mol. Cell. Biol. |volume=18 |issue= 11 |pages= 6653-65 |year= 1998 |pmid= 9774680 |doi=  }}
*{{cite journal   |vauthors=Thong MK, Scherer G, Kozlowski K, etal |title=Acampomelic campomelic dysplasia with SOX9 mutation. |journal=Am. J. Med. Genet. |volume=93 |issue= 5 |pages= 421–5 |year= 2000 |pmid= 10951468 |doi=10.1002/1096-8628(20000828)93:5<421::AID-AJMG14>3.0.CO;2-5  }}
*{{cite journal  | author=McDowall S, Argentaro A, Ranganathan S, ''et al.'' |title=Functional and structural studies of wild type SOX9 and mutations causing campomelic dysplasia. |journal=J. Biol. Chem. |volume=274 |issue= 34 |pages= 24023-30 |year= 1999 |pmid= 10446171 |doi=  }}
*{{cite journal   |vauthors=Ninomiya S, Yokoyama Y, Teraoka M, etal |title=A novel mutation (296 del G) of the SOX90 gene in a patient with campomelic syndrome and sex reversal. |journal=Clin. Genet. |volume=58 |issue= 3 |pages= 224–7 |year= 2001 |pmid= 11076045 |doi=10.1034/j.1399-0004.2000.580310.x }}
*{{cite journal | author=Huang W, Zhou X, Lefebvre V, de Crombrugghe B |title=Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer. |journal=Mol. Cell. Biol. |volume=20 |issue= 11 |pages= 4149-58 |year= 2000 |pmid= 10805756 |doi= }}
*{{cite journal   |vauthors=Preiss S, Argentaro A, Clayton A, etal |title=Compound effects of point mutations causing campomelic dysplasia/autosomal sex reversal upon SOX9 structure, nuclear transport, DNA binding, and transcriptional activation. |journal=J. Biol. Chem. |volume=276 |issue= 30 |pages= 27864–72 |year= 2001 |pmid= 11323423 |doi= 10.1074/jbc.M101278200 }}
*{{cite journal | author=Thong MK, Scherer G, Kozlowski K, ''et al.'' |title=Acampomelic campomelic dysplasia with SOX9 mutation. |journal=Am. J. Med. Genet. |volume=93 |issue= 5 |pages= 421-5 |year= 2000 |pmid= 10951468 |doi= }}
*{{cite journal  | author=Ninomiya S, Yokoyama Y, Teraoka M, ''et al.'' |title=A novel mutation (296 del G) of the SOX90 gene in a patient with campomelic syndrome and sex reversal. |journal=Clin. Genet. |volume=58 |issue= 3 |pages= 224-7 |year= 2001 |pmid= 11076045 |doi= }}
*{{cite journal | author=Preiss S, Argentaro A, Clayton A, ''et al.'' |title=Compound effects of point mutations causing campomelic dysplasia/autosomal sex reversal upon SOX9 structure, nuclear transport, DNA binding, and transcriptional activation. |journal=J. Biol. Chem. |volume=276 |issue= 30 |pages= 27864-72 |year= 2001 |pmid= 11323423 |doi= 10.1074/jbc.M101278200 }}
}}
{{refend}}
{{refend}}


== External links ==
== External links ==
* {{MeshName|SOX9+protein,+human}}
* {{MeshName|SOX9+protein,+human}}
* {{UCSC genome browser|SOX9}}
* {{UCSC gene details|SOX9}}


{{Transcription factors|g4}}
{{Sex determination and differentiation}}
{{NLM content}}


{{protein-stub}}
{{NLM content}}
{{Transcription factors}}
[[Category:Transcription factors]]
[[Category:Transcription factors]]
{{WikiDoc Sources}}

Revision as of 06:51, 11 September 2017

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Orthologs
SpeciesHumanMouse
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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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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 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]

Clinical significance

Mutations lead to the skeletal malformation syndrome campomelic dysplasia, frequently with autosomal sex-reversal[2] and cleft palate.[7]

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/intersexuality 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]

Interactions

SOX9 has been shown to interact with Steroidogenic factor 1,[3] MED12[10] and MAF.[11]

See also

References

  1. ↑ 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. PMID 8348155.
  2. ↑ 2.0 2.1 2.2 "Entrez Gene: SOX9 SRY (sex determining region Y)-box 9 (campomelic dysplasia, autosomal sex-reversal)".
  3. ↑ 3.0 3.1 De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck P, Scherer G, Poulat F, Berta P (November 1998). "Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene". Mol. Cell. Biol. 18 (11): 6653–65. doi:10.1128/mcb.18.11.6653. PMC 109250. PMID 9774680.
  4. ↑ 4.0 4.1 4.2 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 (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. PMID 19429785.
  5. ↑ 5.0 5.1 Kim Y, Kobayashi A, Sekido R, DiNapoli L, Brennan J, Chaboissier MC, Poulat F, Behringer RR, Lovell-Badge R, Capel B (June 2006). "Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination". PLoS Biol. 4 (6): e187. doi:10.1371/journal.pbio.0040187. PMC 1463023. PMID 16700629.
  6. ↑ 6.0 6.1 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.
  7. ↑ 7.0 7.1 Dixon MJ, Marazita ML, Beaty TH, Murray JC (March 2011). "Cleft lip and palate: understanding genetic and environmental influences". Nat. Rev. Genet. 12 (3): 167–78. doi:10.1038/nrg2933. PMC 3086810. PMID 21331089.
  8. ↑ 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. PMID 19234473.
  9. ↑ 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". Am. J. Med. Genet. 90 (1): 25–8. doi:10.1002/(SICI)1096-8628(20000103)90:1<25::AID-AJMG5>3.0.CO;2-5. PMID 10602113.
  10. ↑ Zhou R, Bonneaud N, Yuan CX, de Santa Barbara P, Boizet B, Schomber T, Scherer G, Roeder RG, Poulat F, Berta P, Tibor S (July 2002). "SOX9 interacts with a component of the human thyroid hormone receptor-associated protein complex". Nucleic Acids Res. 30 (14): 3245–52. doi:10.1093/nar/gkf443. PMC 135763. PMID 12136106.
  11. ↑ 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. PMID 12381733.

Further reading

External links

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