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Sry

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Title: Sry  
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Subject: Clitoris, Platypus, Transcription factor, Gender, XY sex-determination system, Sex-determination system, Androgen insensitivity syndrome, Testicle, Human gonad, Mill Hill
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Sry

Sex determining region Y
PDB rendering based on 1hry.
Available structures
PDB Ortholog search: RCSB
Identifiers
SRY Gene
RNA expression pattern

Sex-determining region Y protein (SRY) also known as testis-determining factor (TDF) is a protein that in humans is encoded by the SRY gene located in the Y chromosome.[1] This gene is a DNA-binding protein that enhances other transcription factors, or is a transcription factor itself. Its expression directly or indirectly causes the development of primary sex cords, which later develops to seminiferous tubules. These cords form in the central part of the yet-undifferentiated gonad, turning it into a testis. The now induced Leydig cells of the testis then start secreting testosterone while the Sertoli cells produce anti-Mullerian hormone.[2]

SRY is a sex-determining gene on the Y chromosome in the therians (placental mammals and marsupials).[3] This intronless gene encodes a transcription factor that is a member of the SOX (SRY-like box) gene family of DNA-binding proteins. This protein is the therian testis determining factor (TDF), referred to as the sex-determining region Y protein or SRY protein, which initiates male sex determination. Mutations in this gene give rise to XY females with gonadal dysgenesis (Swyer syndrome); translocation of part of the Y chromosome containing this gene to the X chromosome causes XX male syndrome.[4] and some other species.

Certain genes cause chemical reactions that result in the development of testes. Embryos are gonad-ally identical, regardless of genetic sex, until a certain point in development; when the testis-determining factor causes male sex organs to develop. Lack of this factor will cause the embryo to develop as physically female.[2] Mutations in this gene give rise to XY females with gonadal dysgenesis (Swyer syndrome); translocation of part of the Y chromosome containing this gene to the X chromosome causes XX male syndrome.[4]

Older texts discuss a role for the H-Y antigen in the control of testicular development, which was later disproved.

Gene regulation

Sex determination is not highly conserved in the animal kingdom, and model organisms show little resemblance to mammals. Sry gene is only present in mammals, but there is little protein sequence conservation between mammlian species. The only conserved group between mice and mammals is the High Mobility Group (HMG) box region that is responsible for DNA binding. Mutations in this region result is sex reversal.[5] Because there is little conservation, Sry’s promoter, regulatory elements and regulation are not well understood. Within related mammalian groups there are homologies within the first 400-600 base pairs upstream from the translational start site. In vitro studies of human Sry promoter has shown that a region of least 310 bp upstream to translational start site are required for Sry promoter function is activity. This region has two SP1 binding sites, that function as regulatory sites. WT1 and SF1 may work alongside SP1 to regulate Sry 1. It has been shown that dephosphorelated SF-1 and WT1 can bind and activate the Sry promoter in humans. Studies have shown sex reversal when the DAX1 gene is duplicated, and supports the hypothesis that it inhibits SP1 regulation of Sry. Genes FOG2 and GATA4 have been shown to effect activity of Sry. A knockout of FOT2 and GATA4 result in 25% decrease of Sry activity.[6]

Function

During gestation, the cells of the primordial gonad that lie along the urogenital ridge are in a bipotential state, meaning they possess the ability to become either male cells (Sertoli and Leydig cells) or female cells (follicle cells and Theca cells). SRY initiates testis differentiation by activating male-specific transcription factors that allow these bipotential cells to differentiate and proliferate. SRY accomplishes this by upregulating SOX9, a transcription factor with a DNA-binding site very similar to SRY's. SOX9 in turn upregulates fibroblast growth factor 9 (Fgf9), which is necessary for proper Sertoli cell differentiation. Fgf9 then feeds back and upregulates SOX9. SOX9 can also upregulate itself by binding to its own enhancer region (positive feedback loop). Once proper SOX9 levels are reached, the bipotential cells of the gonad begin to differentiate into Sertoli cells. Additionally, cells expressing SRY will continue to proliferate to form the primordial testis. While this constitutes the basic series of events, this brief review should be taken with caution since there are many more factors that influence sex differentiation.

Action in the nucleus

TDF, the protein encoded by the Sry gene, is a transcription factor for testes-determining genes that strongly upregulates the crucial SOX9 protein.[7] The process begins with nuclear localization of TDF by acetylation of the NLS regions, which allows for the binding of importin β and calmodulin to TDF, facilitating its import into the nucleus. Once in the nucleus, TDF and SF1, another transcription factor, bind to TESCO (testis-specific enhancer of Sox9 core), the testes-specific enhancer element of Sox9 gene in Sertoli cell precursors, located upstream of the Sox9 gene transcription start site.[8] Specifically, it is the central HMG region of TDF that binds to the minor groove of the DNA target sequence, causing the DNA to bend and unwind. The establishment of this particular DNA “architecture” facilitates the transcription of the Sox9 gene.[7] SOX9 protein then initiates a positive feedback loop, involving SOX9 acting as its own transcription factor and resulting in the synthesis of large amounts of SOX9.[8]

SOX9 and testes differentiation

The SF1 protein, on its own, leads to minimal transcription of the SOX9 gene in both the XX and XY bipotential gonadal cells along the urogenital ridge. However, binding of the TDF-SF1 complex to the testis-specific enhancer (TESCO) on SOX9 leads to significant up-regulation of the gene in only the XY gonad, while transcription in the XX gonad remains negligible. Part of this up-regulation is accomplished by SOX9 itself through a positive feedback loop; like TDF, SOX9 complexes with SF1 and binds to the TESCO enhancer, leading to further expression of SOX9 in the XY gonad. Two other proteins, FGF9 (fibroblast growth factor 9) and PDG2 (prostaglandin D2), also maintain this up-regulation. Although their exact pathways are not fully understood, they have been proven to be essential for the continued expression of SOX9 at the levels necessary for testes development.[8]

SOX9 and TDF are believed to be responsible for the cell-autonomous differentiation of supporting cell precursors in the gonads into Sertoli cells, the beginning of testes development. These initial Sertoli cells, in the center of the gonad, are hypothesized to be the starting point for a wave of FGF9 that spreads throughout the developing XY gonad, leading to further differentiation of Sertoli cells via the up-regulation of SOX9.[9] SOX9 and TDF are also believed to be responsible for many of the later processes of testis development (such as Leydig cell differentiation, sex cord formation, and formation of testis-specific vasculature), although exact mechanisms remain unclear.[10] It has been shown, however, that SOX9, in the presence of PDG2, acts directly on Amh (encoding anti-Müllerian hormone) and is capable of inducing testis formation in XX mice gonads, indicating its vital to testes development.[9]

Influence on gender

SRY plays an important role in sex determination. A typical male karyotype is XY. Individuals who inherit a normal Y chromosome and multiple X chromosomes are generally male (such as in Klinefelter Syndrome, which has an XXY karyotype). A genetic recombination event known as crossing over can result in karyotypes that do not match their phenotypic expression. Crossing over during paternal meiosis can cause SRY to be transferred from the Y chromosome to the X chromosome.

The Y chromosome, now lacking an SRY gene, can no longer initiate testis development. When this chromosome is inherited, the resulting offspring will have Swyer syndrome, characterized by a male genotype (XY) and a female phenotype. The X chromosome that results from this crossover event now has a SRY gene, and therefore the ability to initiate testis development. Offspring who inherit this chromosome will have an XX genotype, but will be phenotypically male. This condition is called XX male syndrome. The inheritance of an X chromosome containing SRY, followed by the activation of the SRY in only some cells, can cause both testicular and ovarian tissues to form in the same individual, resulting in true hermaphroditism.[11]

While the presence or absence of SRY has generally determined whether or not testis development occurs, it has been suggested that there are other factors that affect the functionality of SRY.[12] Therefore, there are individuals who have SRY, but still develop as females, either because the gene itself is defective or mutated, or because one of the contributing factors is defective.[13] This can happen in individuals exhibiting a XY, XXY, or XX SRY-positive karyotype.

Diseases and defects

Individuals with XY genotype and functional SRY gene can have an outwardly female phenotype due to an underlying androgen insensitivity syndrome (AIS). Individuals with AIS are unable to respond to androgens properly due to a defect in their androgen receptor gene, and affected individuals can have complete or partial AIS.[14] SRY has also been linked to the fact that males are more likely than females to develop dopamine-related diseases such as schizophrenia and Parkinson's disease. SRY encodes a protein that controls the concentration of dopamine, the neurotransmitter that carries signals from the brain that control movement and coordination.[15]

Use in Olympic screening

One of the most controversial uses of this discovery was as a means for gender verification at the Olympic Games, under a system implemented by the International Olympic Committee in 1992. Athletes with an SRY gene were not permitted to participate as females, although all athletes in whom this was "detected" at the 1996 Summer Olympics were ruled false positives and were not disqualified. In the late 1990s, a number of relevant professional societies in United States called for elimination of gender verification, including the American Medical Association, stating that the method used was uncertain and ineffective.[16] The screening was eliminated as of the 2000 Summer Olympics.[16][17][18]

Evolution

SRY may have arisen from a gene duplication of the X chromosome bound gene SOX3, a member of the Sox family.[19] This duplication occurred after the split between monotremes and therians. Monotremes lack SRY and have a ZW-like sex determination system, likely involving DMRT1, whereas therians (marsupials and placental mammals) use the XY sex determination system.[20] SRY is a rapidly evolving gene.[21] A small number of mammals lack this gene entirely and use an alternative form of sex determination.[22]

Interactions

SRY has been shown to interact with the androgen receptor.[23]

See also

References

Further reading

External links

  • GeneReviews/NCBI/NIH/UW entry on 46,XX Testicular Disorder of Sex Development
  • OMIM entries on 46,XX Testicular Disorder of Sex Development
  • Medical Subject Headings (MeSH)
  • Medical Subject Headings (MeSH)

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