Selected-GenAtlas references SOURCE GeneCards NCBI Gene Swiss-Prot Orphanet Ensembl
HGNC UniGene Nucleotide OMIM UCSC
Home Page
FLASH GENE
Symbol SOX9 contributors: mct/shn - updated : 07-08-2014
HGNC name SRY (sex determining region Y)-box 9
HGNC id 11204
Corresponding disease
CMPD1 campomelic dysplasia
PRS Pierre-Robin sequence, non-syndromic
SRA sex reversal XY, SOX9-related
Location 17q24.3      Physical location : 70.117.160 - 70.122.552
Synonym name
  • SRY (sex-determining region Y)-box 9
  • transcription factor SOX-9
  • campomelic dysplasia, autosomal sex-reversal
  • SRY-related HMG-box, gene 9
  • Synonym symbol(s) CMD1, SRA1, CMPD1
    DNA
    TYPE functioning gene
    STRUCTURE 5.40 kb     3 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Binding site   HRE
    text structure
  • DNA binding to the CCTTGAG sequence
  • potential upstream SOX9 cis-acting regulatory element (SOX9Cre1)
  • MAPPING cloned Y linked N status confirmed
    Map cen - D17S1350 - D17S1304 - SOX9 - D17S1797 - D17S1826 - qter
    Physical map
    KCNJ16 17q23.1-q21.2 potassium inwardly-rectifying channel, subfamily J, member 16 KCNJ2 17q23.1-q24.2 potassium inwardly-rectifying channel, subfamily J, member 2 LOC390810 17 similar to calmodulin - rabbit (tentative sequence) LOC124685 17q25.1 similar to smooth muscle and non-muscle myosin alkali light chain isoform 1 LOC388416 17 LOC388416 SOX9 17q24.3-q25.1 SRY (sex determining region Y)-box 9 (campomelic dysplasia, autosomal sex-reversal) LOC388417 17 LOC388417 SLC39A11 17q25.1 solute carrier family 39 (metal ion transporter), member 11 LOC390811 17 similar to DNA-directed RNA polymerases III 12.5 kDa polypeptide (RNA polymerase III C11 subunit) (HsC11p) (hRPC11) (My010 protein) SSTR2 17q24.3-q25 somatostatin receptor 2 COG1 17q25.1 component of oligomeric golgi complex 1 FLJ14775 17q25.1 hypothetical protein FLJ14775 HLC-8 17q25.1 lung cancer-related protein 8 LOC390812 17 similar to cleavage and polyadenylation specific factor 4; musculus clipper/cleavage and polyadenylation specificity factor 30 kDa subunit; cleavage and polyadenylation specific factor 4, 30kD subunit CDC42EP4 17q24-q25 CDC42 effector protein (Rho GTPase binding) 4 SDK2 17q21.31 sidekick homolog 2 (chicken) LOC388418 17 hypothetical gene supported by AL833395 FLJ40319 17q25.2 hypothetical protein FLJ40319 RPL38 17q22 ribosomal protein L38 TTYH2 17q24 Tweety homolog 2 (Drosophila) DNAI2 17q25 dynein, axonemal, intermediate polypeptide 2 FLJ37300 17q25.2 hypothetical protein FLJ37300 LOC388419 17 similar to galectin 3 binding protein; L3 antigen; Mac-2-binding protein; serum protein 90K
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    3 - 3963 - 509 - 2005 15717285
    - - 2076 - - testis 2005 15717285
  • also called Cre1
  • exons 1 to 4, spaced over 104 kb of genomic DNA, a polyadenylation signal, and a poly-A tail
  • EXPRESSION
    Rna function
  • expressed predominantly in mesenchymal condensations throughout the embryo before and during the deposition of cartilage
  • Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart    
    Digestiveintestine   highly Homo sapiens
     salivary gland   highly
    Hearing/Equilibriumear   highly
    Reproductivemale systemtestis  highly Homo sapiens
     male systemprostate  highly
    Visualeye   highly Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivecartilage   
    Epithelialabsorptive excretorydigestive epithelium (mucosa)   Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
     chondrocyte Homo sapiens
    Digestiveepithelial cell Homo sapiens
    ReproductiveSertoli cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, fetal
    Text
  • brain, developing gonads, chondrogenic tissues
  • mesenchymal cells
  • earliest stages of renal development within the ureteric tip, the ureter mesenchyme and in a segment-specific manner during nephrogenesis
  • coexpression of SHOX, SOX5, SOX6 and SOX9 in the fetal growth plate
  • PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal nuclear localization signal (NLS)
  • a SOX consensus calmodulin (CaM) binding region
  • one SRY related high mobility group (HMG) domain, E
  • a transactivation domain in the carboxy-terminus (transcription activation)
  • a dimerization domain (for COL11A2, COL9A2) required only for chondrogenesis, and for transcription activation of a chondrocyte-specific chromatin DNA template
  • conjugated Other
    mono polymer dimer
    HOMOLOGY
    interspecies ortholog to Sox9, Musmusculus
    ortholog to Sox9, Rattus norvegicus
    ortholog to SOX9, Pan troglodytes
    intraspecies homolog to SOX10
    Homologene
    FAMILY
  • SRY related HMG box family of transcription factors
  • CATEGORY DNA associated , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,chromatin/chromosome
    text translocated into the nuclei of Sertoli cells within the developing XY gonad, during sex determination
    basic FUNCTION
  • a primary role in skeletal formation
  • a major molecular component of the neuron-glia switch in the developing spinal cord
  • required for the determination of the chondrogenic lineage in cranial neural crest cells
  • modulator of LINE retroposons promoter activity
  • likely involved in the differentiation of Sertoli cells
  • important mediator of the BMP2 and Indian hedgehog (IHH) signaling pathways in osteogenic cells
  • required for cartilage formation : mesenchymal condensation of cartilage primordia and later step transition of chondrocytes into hypertrophic chondrocytes
  • potent activator of the chondrocyte-specific enhancer of COL2A1
  • specific RNA polymerase 2 transcription factor playing an essential role in the pathway of endocardial cushion cell differentiation
  • inhibiting activation of CTNNB1-dependent promoters and stimulating degradation of beta-catenin by the ubiquitination/proteasome pathway to control chondrocyte differentiation
  • contributing to growth regulation by IGFBP7 via inhibition of cell growth and promotion of differentiation
  • key regulator of cartilage matrix genes and chondrogenesis, and of HAPLN1
  • playing a critical role with SOX5 in chondrogenesis
  • required for the development and differentiation of multiple cell lineages
  • having a central position as both a transcriptional target and a regulator of the Wnt pathway in the regulation of intestinal epithelium homeostasis
  • required during sequential steps of the chondrocyte differentiation pathway
  • in prostate basal cells supports the development and maintenance of the luminal epithelium and a subset of prostate cancer cells may escape basal cell requirements through SOX9 expression
  • having a role in the pigmentation
  • required for the differentiation of Paneth cells
  • regulates chondrogenesis by promoting efficient beta-catenin phosphorylation in the nucleus
  • regulating transcription of the AMH gene
  • required for mesenchymal condensation and subsequent chondroblast differentiation
  • key regulator of BEST1 expression and demonstrate for the first time its functional role in the RPE
  • essential for the development of several cell lineages, including Sertoli cells of the testis, chondrocytes, pancreatic progenitors, and oligodendrocytes in the spinal cord
  • essential for formation and maintenance of multipotent neural stem cells
  • a role in the functional link between extrinsic and intrinsic mechanisms of neural stem cells specification and maintenance
  • SOX9 with its close homologue SOX8, plays an essential role in RET signalling
  • acts at multiple steps during kidney organogenesis and SOX8 and SOX9 are key factors within the RET signalling pathway
  • central controller of epithelial branching by allowing GDNF/RET signalling to occur and maintains tip-specific cell identity, thus suppressing the formation of ectopic nephrogenesis in the outer cortex of the kidney
  • important in mesenchymal progenitors for their differentiation into chondrocytes
  • role in differentiated chondrocytes essential for subsequent hypertrophy and sustaining chondrocyte-specific survival mechanisms by binding to the PIK3CApromoter, inducing Akt phosphorylation
  • cooperates with Arid5a to stimulate chondrocyte-specific transcription
  • pPrecise regulation of both induction and silencing of SOX9 is required for the normal development of chondrocytes
  • SNAI2, and SOX9 suffice to convert differentiated mammary epithelial cells to stem cells
  • SNAI2 and SOX9, acting in concert, could function as master regulators of the mammary stem cells state
  • role of SOX9 in luminal progenitor cells in addition to their function in inducing the formation of mammary stem cells
  • important regulatory role of SOX9 and MYOCD in controlling the transcription program during SMC transdifferentiation into chondrocytes
  • antagonism between SOX9 and MYOCD as central regulators in controlling SMC and chondrogenic gene transcription in SMCs in response to injury
  • SOX9 and SNAI2 may play a developmentally conserved role in regulating cell motility
  • as a negative regulator, SOX9 is essentially downregulated in terminally differentiated hypertrophic chondrocytes
  • the transcription factor SOX9, which is linked to regulation of hypoxia-related genes, was identified as a key mediator of upregulation of the oncogene IFIT3
  • SOX4 and SOX9 control formation of primary cilia, which are known signaling regulators
  • ZBTB20 is a key determinant of astrocytogenesis, in which it collaborates with SOX9 and NFIA, and acts in part through direct repression of POU3F2 expression
  • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS development
    text skeletal development
    PATHWAY
    metabolism
    signaling signal transduction
    indian Hedgehog (IHH) signaling pathway, target of signaling by the parathyroid hormone-related polypeptide in the growth plate of endochondral bones
    a component
  • dimerization with COL11A2, COL9A2 necessary for transactivation of targets in chondrocytes but not in testis
  • forms heterodimers with two additional Sox family members, SOX5 and SOX6, and activates the transcription of COL2A1 gene by a binding enhancer
  • necessary for the formation and maintenance of multipotent neural stem cells
  • INTERACTION
    DNA binding to the CCTTGAG sequence
    RNA
    small molecule
    protein
  • steroidogenic factor 1, SF-1
  • heat shock 70 kDa, HSP70
  • thyroid hormone receptor-associated protein complex 230 kDa component, TRAP230
  • c-Maf transcription factor, Lc-Maf
  • cAMP-response element-binding protein (CREB)-binding protein (CBP)/p300
  • SMAD family member 2, Smad2 and SMAD family member 3, Smad3
  • nucleocytoplasmic transport protein importin beta, IPOB
  • with HSPA1A in chondrocytes and testicular cell lines
  • binding as a monomer to the regulatory region of sex-determining factor NR5A1
  • interaction with NFATC1 for endocardial cushion formation
  • interacts with chromatin and activates transcription via regulation of chromatin modification
  • interacting with WNT4 and CTNNB1 (antagonism between SOX9 and CTNNB1 potentially is the molecular mechanism through which the fate of the supporting cell lineage in the gonad is established to drive male or female sex determination)
  • first direct target of CEACAM1 identified in the colon epithelium (SOX9 upregulates CEACAM1 in colonic cells)
  • cAMP responsive element binding protein 1, CREB1
  • interacting with SOX8 (concerted SOX9 and SOX8 function in Sertoli cells is essential for the maintenance of testicular function)
  • scleraxis, Scx and E47
  • interaction with DMRT1 appear to have swapped roles in the regulatory hierarchy of the vertebrate testis
  • binds to the location around the paired SOX site in the BEST1 promoter in RPE cells (
  • SHOX cooperates with SOX5/SOX6 and SOX9 in the activation of the upstream ACAN enhancer(
  • SOX9 activates TES, augmented by NR5A1, suggesting a mechanism for maintenance of SOX9 expression by auto-regulation
  • regulatory interaction between SOX9, WWP2 and MED25 defines the SOX9 transcriptional mechanisms of chondrogenesis in the forming palate (
  • AT rich interactive domain 5A (MRF1-like), ARID5A
  • BMP signal pathway and SOX9 are required for the onset of chondrogenesis, suggesting that BMP4 and SOX9 are candidate regulators of phenotypic change of mesangial cells in the advanced stage of diabetic nephropathy
  • DMRT1 maintains SOX9 and suppresses FOXL2 expression in postnatal Sertoli cells
  • NELL1 is an important growth factor for regulation of osteochondral differentiation, by regulating both RUNX2 and SOX9 expression within the calvarium
  • TWIST1 binds directly to SOX9 and inhibits both SOX9-dependent gene activation and SOX9 binding to target gene enhancer DNA in chondrogenic cells
  • MYOCD suppresses SOX9-mediated chondrogenic gene COL2A1 expression
  • ZAK plays an essential role in the onset of chondrogenesis through triggering the induction of SOX6 expression by SOX9
  • NKX3-2 and SOX9 repress the activity of the PAX3 promoter and NKX3-2 acts as a transcriptional repressor in this process
  • several enhancers contain potential binding sites for SOX9, consistent with its described role as an upstream regulator of ACAN expression
  • TWIST1 bound robustly to the 3'UTR of SOX9, the central initiator of chondrogenesis, suggesting that TWIST1 might directly repress cartilage formation through SOX9
  • SOX9 regulates LRP6, TCF4 expression and WNT/CTNNB1 activation in breast cancer
  • both phosphorylation, and to a lesser extent SUMOylation, of SOX9 results in a physical interaction between SNAI2 and SOX9, and SOX9 phosphorylation is necessary to cooperate with SNAI2 to trigger neural crest cell delamination
  • ERG redirects AR to a set of genes including SOX9 that are not normally androgen stimulated, and SOX9 is a critical downstream effector of ERG in TMPRSS2:ERG fusion-positive prostate cancer (PCa)
  • is a transcriptional regulator of IGFBP4 and SOX9-induced activation of IGFBP4 may be one of the mechanisms by which SOX9 suppresses cell proliferation and progression of colon cancer
  • SOX9 does not affect MYOCD expression but significantly reduces the expression of MYOCD/SRF-dependent smooth muscle genes, suggesting that down-regulation of SOX9 is a prerequisite for MYOCD activity
  • NFE2L1 promotes glial fate under direct SOX9 regulatory control
  • ZBTB20 regulates the terminal differentiation of hypertrophic chondrocytes by repressing SOX9
  • cell & other
    REGULATION
    activated by retinoic acid
    EP300 activates SOX9-dependent transcription during chondrogenesis
    BMP2 (associated with chromatin remodeling and histone modification)
    inhibited by TNFA and IL1
    Other SOX9 expression induced by Sonic Hedgehog
    phosphorylated by cAMP-dependent protein kinase A
  • extracellular signals initiate phosphorylation of SOX9 and its cooperation with SNAI2 to induce neural crest cell (NCC) delamination
  • ASSOCIATED DISORDERS
    corresponding disease(s) CMPD1 , SRA , PRS
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in testes of (SRY)-negative XX males patients
    constitutional       loss of function
    inactivation in round chondrocytes resulted in a loss of COL2A1 expression and in apoptosis
    constitutional     --over  
    induces chondrocytic phenotypic change in the absence of BMP4
    tumoral     --over  
    of SOX9, WNT1, FZD1, and Ki-67 proteins occurred more frequently in human osteosarcoma tissues with an advanced clinical stage
    Susceptibility to inflammatory joint diseases
    Variant & Polymorphism
    Candidate gene
    Marker
  • ONECUT1 and SOX9 are new biomarkers of acinar-to-ductal metaplasia (ADM) and constitute candidate targets for preventive treatment in cases when ADM may lead to cancer
  • Therapy target
    ANIMAL & CELL MODELS
  • mouse embryos deleted for Sox9 after mesenchymal condensations exhibited a severe generalized chondrodysplasia
  • nactivation of Sox9 in neural crest resulted in a complete absence of cartilages and endochondral bones derived from the cranial neural crest
  • ox9-null cranial neural crest cells were unable to contribute chondrogenic mesenchymal condensations
  • mice in which Sox9 was specifically ablated from neural stem cells by the CRE/loxP recombination system exhibit defects in the specification of oligodendrocytes and astrocytes