SOX9

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[7] and, with steroidogenic factor 1, regulates transcription of the anti-Müllerian hormone (AMH) gene.[6]

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.[8] 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.[9] Next, Sox9 activates FGF9 and forms feedforward loops with FGF9[10] and PGD2.[9] 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.[10] The association of SOX-9 and Dax1 actually creates Sertoli cells, another vital process in male development.[11] 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.[12]

Mutations lead to the skeletal malformation syndrome campomelic dysplasia, frequently with autosomal sex-reversal[6] 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 is mostly localised 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]

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;[9] the same is true if Dax1 is not present.[11] 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.[22]

SOX9 has been shown to interact with Steroidogenic factor 1,[8] MED12[23] and MAF.[24]

• SOX genes

• SOX9+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
• SOX9 human gene location in the UCSC Genome Browser.
• SOX9 human gene details in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P48436 (Human Transcription factor SOX-9) at the PDBe-KB.
• Overview of all the structural information available in the PDB for UniProt: Q04887 (Mouse Transcription factor SOX-9) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.