SOX9

转录因子SOX9是一种蛋白质，在人类中由SOX9基因编码，是塞特利氏细胞等细胞的标志物。^[5][6]

SOX9
已知的结构 PDB 直系同源搜索: PDBe RCSB PDBID列表 4EUW
识别号
别名	SOX9；, CMD1, CMPD1, SRA1, SRXX2, SRXY10, SRY-box 9, SRY-box transcription factor 9
外部ID	OMIM：608160 MGI：98371 HomoloGene：294 GeneCards：SOX9
基因位置（人类） 染色体 17号染色体[1] 基因座 17q24.3 起始 72,121,020 bp[1] 终止 72,126,416 bp[1]
基因位置（小鼠） 染色体 小鼠11号染色体[2] 基因座 11 E2|11 77.27 cM 起始 112,673,050 bp[2] 终止 112,678,586 bp[2]
RNA表达模式
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基因本体 分子功能 • DNA结合转录因子活性 • DNA-binding transcription activator activity, RNA polymerase II-specific • core promoter sequence-specific DNA binding • 蛋白激酶活性 • protein kinase A catalytic subunit binding • beta-catenin binding • pre-mRNA intronic binding • chromatin binding • 血浆蛋白结合 • DNA结合 • sequence-specific DNA binding • transcription cis-regulatory region binding • bHLH transcription factor binding • 核心启动子近端区域序列特异性DNA结合 • protein heterodimerization activity • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding • DNA-binding transcription factor activity, RNA polymerase II-specific • RNA polymerase II cis-regulatory region sequence-specific DNA binding 细胞组分 • 细胞核 • 转录调节复合物 • 核质 • 大分子复合体 生物学过程 • 骨骼系统的发生 • cellular response to retinoic acid • bronchus cartilage development • positive regulation of protein phosphorylation • heart valve development • limb bud formation • positive regulation of protein catabolic process • regulation of transcription by RNA polymerase II • ureter morphogenesis • negative regulation of immune system process • chondrocyte development • positive regulation of cell proliferation involved in heart morphogenesis • oligodendrocyte differentiation • chondrocyte hypertrophy • prostate gland development • lung smooth muscle development • 乳腺发育 • negative regulation of ossification • negative regulation of photoreceptor cell differentiation • cellular response to mechanical stimulus • intrahepatic bile duct development • regulation of cell adhesion • negative regulation of chondrocyte differentiation • positive regulation of mesenchymal cell proliferation • astrocyte fate commitment • positive regulation of chondrocyte differentiation • 精子发生 • prostate gland morphogenesis • negative regulation of epithelial cell proliferation • lung epithelial cell differentiation • chondrocyte differentiation involved in endochondral bone morphogenesis • negative regulation of canonical Wnt signaling pathway • endocrine pancreas development • negative regulation of cell population proliferation • regulation of apoptotic process • cellular response to transforming growth factor beta stimulus • negative regulation of mesenchymal cell apoptotic process • 染色体重建 • negative regulation of myoblast differentiation • positive regulation of branching involved in ureteric bud morphogenesis • cell fate commitment • regulation of transcription, DNA-templated • epidermal growth factor receptor signaling pathway • 成骨作用 • regulation of cell proliferation involved in tissue homeostasis • ureter smooth muscle cell differentiation • ERK1 and ERK2 cascade • notochord development • positive regulation of epithelial cell migration • Sertoli cell differentiation • male sex determination • negative regulation of gene expression • transcription, DNA-templated • metanephric nephron tubule formation • positive regulation of transcription, DNA-templated • 心脏发育 • regulation of branching involved in lung morphogenesis • ureter urothelium development • branching involved in ureteric bud morphogenesis • 软骨生成 • Harderian gland development • positive regulation of kidney development • central nervous system development • heart valve formation • positive regulation of cartilage development • tissue homeostasis • metanephric tubule development • negative regulation of biomineral tissue development • endochondral bone morphogenesis • trachea cartilage development • male germ-line sex determination • 泪腺的发生 • Notch信号通路 • hair follicle development • 细胞分化 • 输尿管的发生 • regulation of cell cycle process • male gonad development • positive regulation of epithelial cell proliferation • cell fate specification • intestinal epithelial structure maintenance • positive regulation of extracellular matrix assembly • extracellular matrix organization • negative regulation of apoptotic process • negative regulation of transcription by RNA polymerase II • Sertoli cell development • positive regulation of mesenchymal stem cell differentiation • retina development in camera-type eye • cellular response to interleukin-1 • 上皮-间充质转换 • homeostasis of number of cells within a tissue • negative regulation of transcription, DNA-templated • cAMP-mediated signaling • cartilage condensation • positive regulation of male gonad development • nucleosome assembly • negative regulation of bone mineralization • morphogenesis of a branching epithelium • neural crest cell development • Akt/PKB信号通路 • somatic stem cell population maintenance • otic vesicle formation • otic vesicle development • endocardial cushion morphogenesis • cellular response to epidermal growth factor stimulus • positive regulation of epithelial cell differentiation • renal vesicle induction • positive regulation of gene expression • regulation of epithelial cell proliferation involved in lung morphogenesis • regulation of cell population proliferation • heart valve morphogenesis • 细胞骨架组织 • cochlea morphogenesis • positive regulation of cell population proliferation • epithelial cell proliferation involved in prostatic bud elongation • retinal rod cell differentiation • protein localization to nucleus • regulation of cell differentiation • positive regulation of phosphatidylinositol 3-kinase signaling • cellular response to heparin • negative regulation of epithelial cell differentiation • epithelial tube branching involved in lung morphogenesis • 信号转导 • positive regulation of transcription by RNA polymerase II • negative regulation of pri-miRNA transcription by RNA polymerase II • chondrocyte differentiation • neural crest cell fate specification • cellular response to BMP stimulus • cell-cell adhesion • transcription initiation from RNA polymerase II promoter • protein-containing complex assembly • anterior head development • morphogenesis of an epithelium • aortic valve morphogenesis • 基因调节 Sources:Amigo / QuickGO
直系同源
物种	人类	小鼠
Entrez	6662	20682
Ensembl	ENSG00000125398	ENSMUSG00000000567
UniProt	P48436	Q04887
mRNA​序列	NM_000346	NM_011448
蛋白序列	NP_000337	NP_035578
基因位置​（UCSC）	Chr 17: 72.12 – 72.13 Mb	Chr 11: 112.67 – 112.68 Mb
PubMed​查找	[3]	[4]
维基数据
查看/编辑人类 查看/编辑小鼠

功能

SOX9识别序列CCTTGAG，与其他HMG-box类DNA结合蛋白一起发挥作用。它由增殖但非肥大软骨细胞表达，对于前体细胞分化为软骨细胞至关重要^[7]，并且与类固醇生成因子1一起调节抗苗勒氏激素（AMH）基因的转录。^[6]

SOX9也在雄性性发育中扮演着关键角色；通过与Sf1协同作用，SOX9可以在赛特利氏细胞中产生AMH，以抑制女性生殖系统的形成。^[8] 它还与其他几个基因互作，以促进雄性生殖器官的发育。该过程始于转录因子睾丸决定因子（由Y染色体的性别决定区SRY编码）通过结合在该基因上游的一段增强子序列，激活SOX9活性。^[9] 接着，SOX9激活FGF9并与FGF9形成前馈回路^[10]和PGD2。^[9]

这些回路对于产生SOX9十分重要；如果没有这些回路，SOX9将会耗尽，且几乎可以确定会出现女性的发育。SOX9激活FGF9启动男性发育中的重要过程，例如创建睾丸索以及塞特利氏细胞的增殖。^[10] SOX9与Dax1的结合实际上会产生塞尔托利细胞，这是雄性发育中另一个重要的过程。^[11] 在大脑发育中，其小鼠直系同源基因SOX9诱导Wwp1、Wwp2和miR-140的表达，以调节新生神经细胞进入皮质板，并调节皮质神经元的轴突分支和轴突形成。^[12]

Sox9，也被称为SRY-Box转录因子9，是性别决定中一个重要的基因。SOX家族基因全都是Y染色体性别决定因子SRY的转录因子。SRY基因编码SOX转录因子，同时它上调Sox9。Sox9之后启动Fgf9，即成纤维细胞生长因子9，这也是雄性腺体形成过程中的另一个关键转录因子。Fgf9通过正向前馈级联上调Sox9，这导致塞特利氏细胞分化，最终形成睾丸。^[13]

SOX9是Notch信号转导途径以及Hedgehog途径的标靶，^[14]并在调节神经干细胞命运中扮演角色。体内和体外研究显示SOX9对神经元生成具有负调控作用，对胶质细胞生成和干细胞存活具有正调控作用。^[15]

在成年关节软骨细胞中，通过siRNA介导的SOX9或RTL3敲低会导致另一个基因的下调，以及II型胶原蛋白（COL2A1）mRNA和蛋白表达的降低。^[16]

在缺乏SRY的情况下，于XY性腺中过度表现SOX9可以进一步促进雄性性别决定和睾丸发育。^[17] 亦可发现，在XX性腺别构表现SOX9，即使在缺乏SRY的情况下亦会导致睾丸的发育。^[18] 这两者皆证明，SOX9在缺乏SRY的情况下，无论在XX或XY性腺中，仍将持续于睾丸发育、睾丸分化和性别决定上发挥关键作用。亦有详细说明SOX9可替代SRY的功能。^[19][20]

临床意义

突变会导致骨骼畸形综合征弯骨发育不全，通常伴有常染色体性别反转^[6]和裂颚。^[21]

SOX9位于人类17q24的基因沙漠中。SOX9两侧距转录单位超过1Mb的高度保守非编码元件的缺失、被易位断点干扰以及单点突变，都与皮埃尔·罗宾序列相关，且常伴有颚裂。^[21][22]

SOX9蛋白已被认为与多种实质固态瘤(solid tumors)的发生和进展有关。^[23] 其作为形态发生的主调节因子在人体发育过程中的角色，使其成为恶性组织中扰动的理想候选者。具体而言，SOX9似乎在前列腺、^[24]结直肠、^[25]乳腺^[26]和其他癌症中诱导侵袭性和治疗抵抗性，从而促进致命的转移。^[27]SOX9的许多这些致癌效应似乎是剂量依赖的。^[28][24][23]

SOX9 的定位和动态

SOX9 主要定位于细胞核中，且具有高度的流动性。对软骨细胞系的研究显示，近50%的 SOX9 与 DNA 结合，并且直接受到外部因素的调控。其在 DNA 上的驻留半衰期约为14秒。^[29]

在性别分化中的角色

SOX9帮助引导SRY在性别分化中的激活。SOX9或任何相关基因的突变可能导致性别逆转。如果SOX9激活的FGF9不存在，具有X和Y染色体的胎儿将成为女性。^[9] 如果DAX1不存在，情况也是如此。^[11] 相关现象可能由于SRY在XX男性综合征中的不寻常活动引起，通常是当它转位到X染色体上并且其活动仅在某些细胞中被激活时。^[30] SOX9的突变或缺失可能导致XY胎儿成为女性，因为SOX9是一个关键的效应基因，通过SRY基因作用来分化支持细胞并推动男性睾丸的形成。^[13]

相互作用

已显示SOX9与类固醇生成因子1^[8]、MED12^[31]、MAF^[32]、SWI/SNF、MLL3和MLL4发生相互作用。^[33]

基因敲除模型

SOX9的功能丧失突变可能导致弯曲肢体发育不全症（CD），这是由于影响蛋白质功能的突变和破坏基因表达的易位。已经有SOX9基因敲除小鼠显示出中风恢复的改善，特别是在抑制如NOGO和硫酸软骨素蛋白聚糖（CSPGs）等轴突萌芽抑制剂时。SOX9的去除导致CSPG水平降低，这增加了组织保护并改善了中风后的神经恢复。这些SOX9基因敲除小鼠促进修复性轴突萌芽、神经保护和中风后的恢复。^[34]

参见

• SOX基因家族

进一步阅读

• Ninomiya S, Narahara K, Tsuji K, Yokoyama Y, Ito S, Seino Y. Acampomelic campomelic syndrome and sex reversal associated with de novo t(12;17) translocation. American Journal of Medical Genetics. March 1995, 56 (1): 31–34. PMID 7747782. doi:10.1002/ajmg.1320560109.
• Lefebvre V, de Crombrugghe B. Toward understanding SOX9 function in chondrocyte differentiation. Matrix Biology. March 1998, 16 (9): 529–540. PMID 9569122. doi:10.1016/S0945-053X(98)90065-8.
• Harley VR. The Molecular Action of Testis-Determining Factors SRY and SOX9. The Genetics and Biology of Sex Determination. Novartis Foundation Symposia 244. 2002: 57–66; discussion 66–7, 79–85, 253–7. ISBN 9780470843468. PMID 11990798. doi:10.1002/0470868732.ch6.
• Kwok C, Weller PA, Guioli S, Foster JW, Mansour S, Zuffardi O, Punnett HH, Dominguez-Steglich MA, Brook JD, Young ID. Mutations in SOX9, the gene responsible for Campomelic dysplasia and autosomal sex reversal. American Journal of Human Genetics. November 1995, 57 (5): 1028–1036. PMC 1801368 . PMID 7485151.
• Foster JW, Dominguez-Steglich MA, Guioli S, Kwok C, Weller PA, Stevanović M, Weissenbach J, Mansour S, Young ID, Goodfellow PN. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature. December 1994, 372 (6506): 525–530. Bibcode:1994Natur.372..525F. PMID 7990924. S2CID 1472426. doi:10.1038/372525a0.
• Wagner T, Wirth J, Meyer J, Zabel B, Held M, Zimmer J, Pasantes J, Bricarelli FD, Keutel J, Hustert E, Wolf U, Tommerup N, Schempp W, Scherer G. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell. December 1994, 79 (6): 1111–1120. PMID 8001137. S2CID 24982682. doi:10.1016/0092-8674(94)90041-8.
• Südbeck P, Schmitz ML, Baeuerle PA, Scherer G. Sex reversal by loss of the C-terminal transactivation domain of human SOX9. Nature Genetics. June 1996, 13 (2): 230–232. PMID 8640233. S2CID 22617889. doi:10.1038/ng0696-230.
• Cameron FJ, Hageman RM, Cooke-Yarborough C, Kwok C, Goodwin LL, Sillence DO, Sinclair AH. A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal. Human Molecular Genetics. October 1996, 5 (10): 1625–1630. PMID 8894698. doi:10.1093/hmg/5.10.1625 .
• Meyer J, Südbeck P, Held M, Wagner T, Schmitz ML, Bricarelli FD, Eggermont E, Friedrich U, Haas OA, Kobelt A, Leroy JG, Van Maldergem L, Michel E, Mitulla B, Pfeiffer RA, Schinzel A, Schmidt H, Scherer G. Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations. Human Molecular Genetics. January 1997, 6 (1): 91–98. PMID 9002675. doi:10.1093/hmg/6.1.91 .
• Cameron FJ, Sinclair AH. Mutations in SRY and SOX9: testis-determining genes. Human Mutation. 1997, 9 (5): 388–395. PMID 9143916. S2CID 45387678. doi:10.1002/(SICI)1098-1004(1997)9:5<388::AID-HUMU2>3.0.CO;2-0.
• Wunderle VM, Critcher R, Hastie N, Goodfellow PN, Schedl A. Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia. Proceedings of the National Academy of Sciences of the United States of America. September 1998, 95 (18): 10649–10654. Bibcode:1998PNAS...9510649W. PMC 27949 . PMID 9724758. doi:10.1073/pnas.95.18.10649 .
• 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. November 1998, 18 (11): 6653–6665. PMC 109250 . PMID 9774680. doi:10.1128/mcb.18.11.6653.
• McDowall S, Argentaro A, Ranganathan S, Weller P, Mertin S, Mansour S, Tolmie J, Harley V. Functional and structural studies of wild type SOX9 and mutations causing campomelic dysplasia. The Journal of Biological Chemistry. August 1999, 274 (34): 24023–24030. PMID 10446171. doi:10.1074/jbc.274.34.24023 .
• Huang W, Zhou X, Lefebvre V, de Crombrugghe B. Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer. Molecular and Cellular Biology. June 2000, 20 (11): 4149–4158. PMC 85784 . PMID 10805756. doi:10.1128/MCB.20.11.4149-4158.2000.
• Thong MK, Scherer G, Kozlowski K, Haan E, Morris L. Acampomelic campomelic dysplasia with SOX9 mutation. American Journal of Medical Genetics. August 2000, 93 (5): 421–425. PMID 10951468. doi:10.1002/1096-8628(20000828)93:5<421::AID-AJMG14>3.0.CO;2-5.
• Ninomiya S, Yokoyama Y, Teraoka M, Mori R, Inoue C, Yamashita S, Tamai H, Funato M, Seino Y. A novel mutation (296 del G) of the SOX90 gene in a patient with campomelic syndrome and sex reversal. Clinical Genetics. September 2000, 58 (3): 224–227. PMID 11076045. S2CID 28618271. doi:10.1034/j.1399-0004.2000.580310.x.
• Preiss S, Argentaro A, Clayton A, John A, Jans DA, Ogata T, Nagai T, Barroso I, Schafer AJ, Harley VR. Compound effects of point mutations causing campomelic dysplasia/autosomal sex reversal upon SOX9 structure, nuclear transport, DNA binding, and transcriptional activation. The Journal of Biological Chemistry. July 2001, 276 (30): 27864–27872. PMID 11323423. doi:10.1074/jbc.M101278200 .