Transcription factor SOX-9 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''SOX9''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
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
Chondrocytes (, from Greek χόνδρος, ''chondros'' = cartilage + κύτος, ''kytos'' = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteog ...
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
The Y chromosome is one of two sex chromosomes (allosomes) in therian mammals, including humans, and many other animals. The other is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or abs ...
) activates SOX-9 activity by binding to an
enhancer sequence
upstream
Upstream may refer to:
* Upstream (bioprocess)
* ''Upstream'' (film), a 1927 film by John Ford
* Upstream (networking)
* ''Upstream'' (newspaper), a newspaper covering the oil and gas industry
* Upstream (petroleum industry)
* Upstream (software ...
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.
Clinical significance
Mutations lead to the skeletal malformation syndrome
campomelic dysplasia
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 diseas ...
, 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
Pierre Robin sequence (; abbreviated PRS) is a congenital defect observed in humans which is characterized by facial abnormalities. The three main features are micrognathia (abnormally small mandible), which causes glossoptosis (downwardly displa ...
, 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 localisation and dynamics
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.
Role in sex reversal
Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s in Sox9 or any associated genes can cause reversal of sex and
hermaphroditism (or
intersex
Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical b ...
uality in humans). If Fgf9, which is activated by Sox9, is not present, a
fetus
A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal dev ...
with both X and Y
chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...
s can develop female gonads;
the same is true if
Dax1 is not present.
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.
Interactions
SOX9 has been shown to
interact
Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...
with
Steroidogenic factor 1,
MED12 and
MAF
MAF may refer to:
Military
* Myanmar Air Force
* Malaysian Armed Forces
* Marine Amphibious Force, a former name for Marine Expeditionary Force, a type of U.S. Marine Corps task force
Organizations
* Majid Al Futtaim Group
* Move America Forw ...
.
See also
*
SOX genes
Further reading
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References
External links
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Transcription factors