SOX9

Transcription factor SOX-9 is a protein that in humans is encoded by the SOX9 gene.

Function
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 and, with steroidogenic factor 1, regulates transcription of the anti-Müllerian hormone (AMH) gene.

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. 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. Next, SOX9 activates FGF9 and forms feedforward loops with FGF9 and PGD2. 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. The association of SOX-9 and Dax1 actually creates Sertoli cells, another vital process in male development. 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.

Sox9, also known as SRY-Box Transcription Factor 9, is an important gene is sex determination. The SOX family of genes are all transcription factors for the Y chromosomal sex-determining factor SRY. The SRY gene encodes the SOX transcription factor while it upregulates Sox9. Sox9 then activates Fgf9, Fibroblast growth factor 9, which is another integral transcription factor in the formation of the male gonads. Fgf9 up-regulates Sox9 in a positive feedforward cascade, this causes the differentiation of sertoli cells leading to the formation of the testis.

SOX-9 is a target of the Notch signaling pathway, as well as the Hedgehog pathway, and plays a role in the regulation of neural stem cell fate. In vivo and in vitro studies show that SOX-9 negatively regulates neurogenesis and positively regulates gliogenesis and stem cell survival.

In adult articular chondrocytes, siRNA-mediated knockdown of SOX-9 or RTL3 results in the downregulation of the other and reduced type II collagen (COL2A1) mRNA and protein expression.

Clinical significance
Mutations lead to the skeletal malformation syndrome campomelic dysplasia, frequently with autosomal sex-reversal and cleft palate.

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.

The SOX9 protein has been implicated in both initiation and progression of multiple solid tumors. 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, colorectal, breast and other cancers, and therefore promotes lethal metastasis. Many of these oncogenic effects of SOX9 appear dose-dependent.

SOX9 localization and dynamics
SOX9 is mostly localizatied 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.

Role in Sexual Differentiation
SOX9 helps channel SRY activation in sexual differentiation. Mutations in SOX9 or any associated genes can cause a reversal of sex. If FGF9, which is activated by SOX9, is not present, a fetus with both X and Y chromosomes will become female. the same is true if DAX1 is not present. The related phenomena can be caused by unusual activity of the SRY in XX male syndrome, usually when it's translocated onto the X-chromosome and its activity is only activated in some cells. Mutation or deletion of SOX9 could cause an XY fetus to be female because SOX9 is a critical effector gene that works because of the SRY gene to differentiate Sertoli cells and drive testis formation in males.

Interactions
SOX9 has been shown to interact with steroidogenic factor 1, MED12, MAF, SWI/SNF, MLL3 and MLL4.

Knock out models
Loss of function mutations with Sox9 can lead to campomelic dysplasia(CD), due to mutations affecting protein functions and translocations that disrupt gene expression. There have been Sox9 knockout mice that have shown improved stroke recovery, especially when inhibiting inhibitors of axonal sprouting such as NOGO and chondroitin sulfate proteoglycans (CSPGs). Sox9 ablation leads to decreased levels of CSPG, which increases tissue sparing and improved post-stroke neurological recovery. These Sox9 knockout mice promote reparative axonal sprouting, neuroprotection and recovery after stroke.