Transcription factor SOX-9 is a protein that in humans is encoded by the SOX9 gene. [5] [6]
Transcription factor SOX-9 is a protein that in humans is encoded by the SOX9 gene. [5] [6]
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]
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. [13]
SOX-9 is a target of the Notch signaling pathway, as well as the Hedgehog pathway, [14] 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. [15]
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. [16]
Mutations lead to the skeletal malformation syndrome campomelic dysplasia, frequently with autosomal sex-reversal [6] and cleft palate. [17]
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. [17] [18]
The Sox9 protein has been implicated in both initiation and progression of multiple solid tumors. [19] 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, [20] colorectal, [21] breast [22] and other cancers, and therefore promotes lethal metastasis. [23] Many of these oncogenic effects of Sox9 appear dose dependent. [24] [20] [19]
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. [25]
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. [26]
Mutation or deletion of Sox9 could cause an XY sex reversal due to the fact that Sox9 is a critical effector gene that works because of the SRY gene to differentiate sertoli cells and drive testis formation in males. 50% of normal Sox9 levels are needed for the formation of testis otherwise male-to-female sex reversal might occur. [27]
SOX9 has been shown to interact with steroidogenic factor 1, [8] MED12, [28] MAF, [29] SWI/SNF, MLL3 and MLL4. [30]
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. [31]
An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal pairs, which may have different structures. The DNA in autosomes is collectively known as atDNA or auDNA.
Sex-determining region Y protein (SRY), or testis-determining factor (TDF), is a DNA-binding protein encoded by the SRY gene that is responsible for the initiation of male sex determination in therian mammals. SRY is an intronless sex-determining gene on the Y chromosome. Mutations in this gene lead to a range of disorders of sex development with varying effects on an individual's phenotype and genotype.
Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system in humans. It is atypical development of gonads in an embryo. One type of gonadal dysgenesis is the development of functionless, fibrous tissue, termed streak gonads, instead of reproductive tissue. Streak gonads are a form of aplasia, resulting in hormonal failure that manifests as sexual infantism and infertility, with no initiation of puberty and secondary sex characteristics.
Campomelic dysplasia (CMD) is a genetic disorder characterized by bowing of the long bones and many other skeletal and extraskeletal features. It can be lethal in the neonatal period due to respiratory insufficiency, but the severity of the disease is variable, and a significant proportion of patients survive into adulthood. The name is derived from the Greek roots campo, meaning bent, and melia, meaning limb. An unusual aspect of the disease is that up to two-thirds of affected 46,XY genotypic males display a range of disorders of sexual development (DSD) and genital ambiguities or may even develop as normal phenotypic females as in complete 46 XY sex reversal. An atypical form of the disease with absence of bowed limbs is called, prosaically, acampomelic campomelic dysplasia (ACD) and is found in about 10% of patients, particularly those surviving the neonatal period.
In developmental biology, the cells that give rise to the gametes are often set aside during embryonic cleavage. During development, these cells will differentiate into primordial germ cells, migrate to the location of the gonad, and form the germline of the animal.
The sulfate transporter is a solute carrier family protein that in humans is encoded by the SLC26A2 gene. SLC26A2 is also called the diastrophic dysplasia sulfate transporter (DTDST), and was first described by Hästbacka et al. in 1994. A defect in sulfate activation described by Superti-Furga in achondrogenesis type 1B was subsequently also found to be caused by genetic variants in the sulfate transporter gene. This sulfate (SO42−) transporter also accepts chloride, hydroxyl ions (OH−), and oxalate as substrates. SLC26A2 is expressed at high levels in developing and mature cartilage, as well as being expressed in lung, placenta, colon, kidney, pancreas and testis.
The steroidogenic factor 1 (SF-1) protein is a transcription factor involved in sex determination by controlling the activity of genes related to the reproductive glands or gonads and adrenal glands. This protein is encoded by the NR5A1 gene, a member of the nuclear receptor subfamily, located on the long arm of chromosome 9 at position 33.3. It was originally identified as a regulator of genes encoding cytochrome P450 steroid hydroxylases, however, further roles in endocrine function have since been discovered.
WNT4 is a secreted protein that, in humans, is encoded by the WNT4 gene, found on chromosome 1. It promotes female sex development and represses male sex development. Loss of function may have consequences, such as female to male sex reversal.
SRY -box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells.
Forkhead box protein L2 is a protein that in humans is encoded by the FOXL2 gene.
Indian hedgehog homolog (Drosophila), also known as IHH, is a protein which in humans is encoded by the IHH gene. This cell signaling protein is in the hedgehog signaling pathway. The several mammalian variants of the Drosophila hedgehog gene (which was the first named) have been named after the various species of hedgehog; the Indian hedgehog is honored by this one. The gene is not specific to Indian hedgehogs.
Transcription factor SOX-4 is a protein that in humans is encoded by the SOX4 gene.
Glia-activating factor is a protein that in humans is encoded by the FGF9 gene.
Transcription factor SOX-3 is a protein that in humans is encoded by the SOX3 gene. This gene encodes a member of the SOX family of transcription factors involved in the regulation of embryonic brain development and in determination of cell fate. The encoded protein acts as a transcriptional activator.
Transcription factor SOX-5 is a protein that in humans is encoded by the SOX5 gene.
Transcription factor SOX-18 is a protein that in humans is encoded by the SOX18 gene.
Doublesex and mab-3 related transcription factor 1, also known as DMRT1, is a protein which in humans is encoded by the DMRT1 gene.
Transcription factor SOX-11 is a protein that in humans is encoded by the SOX11 gene.
Transcription factor SOX-14 is a protein that in humans is encoded by the SOX14 gene.
Peter Anthony Koopman is an Australian biologist best known for his role in the discovery and study of the mammalian Y-chromosomal sex-determining gene, Sry.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.
