Sex-determining region Y protein

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Testis determining factor
)
SRY
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl
UniProt
RefSeq (mRNA)

NM_003140

NM_011564

RefSeq (protein)

NP_003131

NP_035694

Location (UCSC)Chr Y: 2.79 – 2.79 MbChr Y: 2.66 – 2.66 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

In humans, the SRY gene is located on short (p) arm of the Y chromosome at position 11.2

Sex-determining region Y protein (SRY), or testis-determining factor (TDF), is a

placental mammals and marsupials).[5] SRY is an intronless sex-determining gene on the Y chromosome.[6] Mutations in this gene lead to a range of disorders of sex development with varying effects on an individual's phenotype and genotype
.

SRY is a member of the

secondary sexual characteristics
of males.

Gene evolution and regulation

Evolution

SRY may have arisen from a

placentals, which use SRY in their sex determination process, the action of SRY differs between species.[10] The gene sequence also changes; while the core of the gene, the high-mobility group (HMG) box, is conserved between species, other regions of the gene are not.[10] SRY is one of only four genes on the human Y chromosome that have been shown to have arisen from the original Y chromosome.[13] The other genes on the human Y chromosome arose from an autosome that fused with the original Y chromosome.[13]

Regulation

SRY has little in common with sex determination genes of other model organisms, therefore, mice are the main model research organisms that can be utilized for its study. Understanding its regulation is further complicated because even between mammalian species, there is little protein

WT1), to the human promoter sequence, influence expression of SRY.[14]

The promoter region has two Sp1 binding sites, at -150 and -13 that function as regulatory sites. Sp1 is a transcription factor that binds GC-rich consensus sequences, and mutation of the SRY binding sites leads to a 90% reduction in gene transcription. Studies of SF1 have resulted in less definite results. Mutations of SF1 can lead to sex reversal, and deletion can lead to incomplete gonad development. However, it is not clear how SF1 interacts with the SR1 promoter directly.

zinc fingers and an N-terminal Pro/Glu-rich region and primarily functions as an activator. Mutation of the zinc fingers or inactivation of WT1 results in reduced male gonad size. Deletion of the gene resulted in complete sex reversal. It is not clear how WT1 functions to up-regulate SRY, but some research suggests that it helps stabilize message processing.[15] However, there are complications to this hypothesis, because WT1 also is responsible for expression of an antagonist of male development, DAX1, which stands for dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1. An additional copy of DAX1 in mice leads to sex reversal. It is not clear how DAX1 functions, and many different pathways have been suggested, including SRY transcriptional destabilization and RNA binding. There is evidence from work on suppression of male development that DAX1 can interfere with function of SF1, and in turn transcription of SRY by recruiting corepressors.[14]

There is also evidence that GATA binding protein 4 (GATA4) and FOG2 contribute to activation of SRY by associating with its promoter. How these proteins regulate SRY transcription is not clear, but FOG2 and GATA4 mutants have significantly lower levels of SRY transcription.[16] FOGs have zinc finger motifs that can bind DNA, but there is no evidence of FOG2 interaction with SRY. Studies suggest that FOG2 and GATA4 associate with nucleosome remodeling proteins that could lead to its activation.[17]

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 leads to the upregulation of fibroblast growth factor 9 (Fgf9
), which in turn leads to further upregulation of SOX9. 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. This brief review constitutes the basic series of events, but there are many more factors that influence sex differentiation.

Action in the nucleus

The SRY protein consists of three main regions. The central region encompasses the

prostaglandin D synthase (Ptgds) gene. SOX9 binding to the enhancer near the Amh promoter allows for the synthesis of Amh while SOX9 binding to the Ptgds gene allows for the production of prostaglandin D2 (PGD2). The reentry of SOX9 into the nucleus is facilitated by autocrine or paracrine signaling conducted by PGD2.[18] 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.[15]

SOX9 and testes differentiation

The SF-1 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 SRY-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 SRY, 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.[7]

SOX9 and SRY 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.[19] SOX9 and SRY 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.[20] 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 it is vital to testes development.[19]

SRY disorders' influence on sex expression

Embryos are gonadally identical, regardless of genetic sex, until a certain point in development when the testis-determining factor causes male sex organs to develop. A typical male karyotype is XY, whereas a female's is XX. There are exceptions, however, in which SRY plays a major role. Individuals with Klinefelter syndrome inherit a normal Y chromosome and multiple X chromosomes, giving them a karyotype of XXY. These persons are male.[21] Atypical genetic recombination during crossover, when a sperm cell is developing, can result in karyotypes that are not typical for their phenotypic expression.

Most of the time, when a developing sperm cell undergoes crossover during meiosis, the SRY gene stays on the Y chromosome. If the SRY gene is transferred to the X chromosome instead of staying on the Y chromosome, testis development will no longer occur. This is known as

Swyer syndrome, characterized by an XY karyotype and a female phenotype. Individuals who have this syndrome have normally formed uteri and fallopian tubes, but the gonads are not functional. Swyer syndrome individuals are usually considered as females.[22] On the other spectrum, XX male syndrome occurs when a body has 46:XX Karyotype and SRY attaches to one of them through translocation. People with XX male syndrome have a XX Karyotype but are male.[23] Individuals with either of these syndromes can experience delayed puberty, infertility, and growth features of the opposite sex they identify with. XX male syndrome expressers may develop breasts, and those with Swyer syndrome may have facial hair.[22][24]

Klinefelter Syndrome
  • Inherit a normal Y chromosome and multiple X chromosomes, giving persons a karyotype of XXY.
  • Persons with this are considered male.
Swyer Syndrome
  • SRY gene is transferred to the X chromosome instead of staying on the Y chromosome, testis development will no longer occur.
  • Characterized by an XY karyotype and female phenotype.
  • Individuals have normally formed uteri and fallopian tubes, but the gonads are not functional.
XX Male Syndrome
  • Characterized by a body that has 46:XX Karyotype and SRY attaches to one of them through translocation.
  • Individuals have XX karyotype and male phenotype.

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.[25] Therefore, there are individuals who have the SRY gene, but still develop as females, either because the gene itself is defective or mutated, or because one of the contributing factors is defective.[26] This can happen in individuals exhibiting a XY, XXY, or XX SRY-positive karyotype.

Additionally, other sex determining systems that rely on SRY beyond XY are the processes that come after SRY is present or absent in the development of an embryo. In a normal system, if SRY is present for XY, SRY will activate the medulla to develop gonads into testes. Testosterone will then be produced and initiate the development of other male sexual characteristics. Comparably, if SRY is not present for XX, there will be a lack of the SRY based on no Y chromosome. The lack of SRY will allow the cortex of embryonic gonads to develop into ovaries, which will then produce estrogen, and lead to the development of other female sexual characteristics.[27]

Role in other diseases

SRY has been shown to

Hirschsprung disease, or congenital megacolon in humans.[31] There is also a link between SRY encoded transcription factor SOX9 and campomelic dysplasia (CD).[32] This missense mutation causes defective chondrogenesis, or the process of cartilage formation, and manifests as skeletal CD.[33] Two thirds of 46,XY individuals diagnosed with CD have fluctuating amounts of male-to-female sex reversal.[32]

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. Specifically, eight female participants (out of a total of 3387) at these games were found to have the SRY gene. However, after further investigation of their genetic conditions, all these athletes were verified as female and allowed to compete. These athletes were found to have either partial or full androgen insensitivity, despite having an SRY gene, making them externally phenotypically female.[34] 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.[35] Chromosomal screening was eliminated as of the 2000 Summer Olympics,[35][36][37] but this was later followed by other forms of testing based on hormone levels.[38]

Ongoing research

Despite the progress made during the past several decades in the study of sex determination, the SRY gene, and its protein, work is still being conducted to further understanding in these areas. There remain factors that need to be identified in the sex-determining molecular network, and the chromosomal changes involved in many other human sex-reversal cases are still unknown. Scientists continue to search for additional sex-determining genes, using techniques such as microarray screening of the genital ridge genes at varying developmental stages, mutagenesis screens in mice for sex-reversal phenotypes, and identifying the genes that transcription factors act on using chromatin immunoprecipitation.[15]

See also

References

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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000069036 - Ensembl, May 2017
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  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  22. ^ a b "Swyer syndrome". Genetics Home Reference. National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services. Retrieved 3 March 2020.
  23. ^ "XX Male Syndrome {". encyclopedia.com. Retrieved 3 March 2020.
  24. ^ "46,XX testicular disorder of sex development". Genetics Home Reference. National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services. Retrieved 3 March 2020.
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  33. ^ "OMIM Entry – # 114290 – CAMPOMELIC DYSPLASIA". omim.org. Retrieved 29 February 2020.
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  35. ^ a b Facius GM (1 August 2004). "The Major Medical Blunder of the 20th Century". Gender Testing. facius-homepage.dk. Archived from the original on 26 January 2010. Retrieved 12 June 2011.
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Further reading

External links