Sex-determining region Y protein
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Location (UCSC) | Chr Y: 2.79 – 2.79 Mb | Chr Y: 2.66 – 2.66 Mb | |||||||
PubMed search | [3] | [4] |
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Sex-determining region Y protein (SRY), or testis-determining factor (TDF), is a
SRY is a member of the
Gene evolution and regulation
Evolution
SRY may have arisen from a
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
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.
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
Action in the nucleus
The SRY protein consists of three main regions. The central region encompasses the
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
Klinefelter Syndrome |
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Swyer Syndrome |
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XX Male Syndrome |
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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
Use in Olympic screening
One of the most controversial uses of this discovery was as a means for
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
- ^ a b c GRCh38: Ensembl release 89: ENSG00000184895 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000069036 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ PMID 21062860.
- ^ Mittwoch U (October 1988). "The race to be male". New Scientist. 120 (1635): 38–42.
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- ^ PMID 22179516.
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- ^ "Klinefelter syndrome". Genetics Home Reference. National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services. Retrieved 3 March 2020.
- ^ 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.
- ^ "XX Male Syndrome {". encyclopedia.com. Retrieved 3 March 2020.
- ^ "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.
- PMID 16996051.
- PMID 19361780.
- OCLC 1004376412.)
{{cite book}}
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- ^ Lister Hill National Center for Biomedical Communications (2008). "Androgen insensitivity syndrome". Genetics Home Reference. U.S. National Library of Medicine.
- S2CID 5939578.
- ^ PMID 9560246.
- ^ PMID 21237710.
- ^ "OMIM Entry – # 114290 – CAMPOMELIC DYSPLASIA". omim.org. Retrieved 29 February 2020.
- ^ "Olympic Gender Testing".
- ^ 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.
- PMID 11252710.
- PMID 12370551.
- ^ "IOC Regulations on Female Hyperandrogenism" (PDF). International Olympic Committee. 22 June 2012. Archived (PDF) from the original on 13 August 2012. Retrieved 9 August 2012.
Further reading
- Haqq CM, King CY, Ukiyama E, Falsafi S, Haqq TN, Donahoe PK, Weiss MA (December 1994). "Molecular basis of mammalian sexual determination: activation of Müllerian inhibiting substance gene expression by SRY". Science. 266 (5190): 1494–500. PMID 7985018.
- Goodfellow PN, Lovell-Badge R (1993). "SRY and sex determination in mammals". Annual Review of Genetics. 27 (1): 71–92. PMID 8122913.
- Hawkins JR (1993). "Mutational analysis of SRY in XY females". Human Mutation. 2 (5): 347–50. S2CID 43503112.
- Harley VR (2002). "The Molecular Action of Testis‐Determining Factors SRY and SOX9". The Genetics and Biology of Sex Determination. Novartis Foundation Symposia. Vol. 244. pp. 57–66, discussion 66–7, 79–85, 253–7. PMID 11990798.
- Jordan BK, Vilain E (2002). "SRY and the Genetics of Sex Determination". Pediatric Gender Assignment. Advances in Experimental Medicine and Biology. Vol. 511. pp. 1–13, discussion 13–4. PMID 12575752.
- Oh HJ, Lau YF (March 2006). "KRAB: a partner for SRY action on chromatin". Molecular and Cellular Endocrinology. 247 (1–2): 47–52. S2CID 19870331.
- Polanco JC, Koopman P (February 2007). "Sry and the hesitant beginnings of male development". Developmental Biology. 302 (1): 13–24. PMID 16996051.
- Hawkins JR, Taylor A, Berta P, Levilliers J, Van der Auwera B, Goodfellow PN (February 1992). "Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal". Human Genetics. 88 (4): 471–4. S2CID 9332496.
- Hawkins JR, Taylor A, Goodfellow PN, Migeon CJ, Smith KD, Berkovitz GD (November 1992). "Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis". American Journal of Human Genetics. 51 (5): 979–84. PMID 1415266.
- Ferrari S, Harley VR, Pontiggia A, Goodfellow PN, Lovell-Badge R, Bianchi ME (December 1992). "SRY, like HMG1, recognizes sharp angles in DNA". The EMBO Journal. 11 (12): 4497–506. PMID 1425584.
- Jäger RJ, Harley VR, Pfeiffer RA, Goodfellow PN, Scherer G (December 1992). "A familial mutation in the testis-determining gene SRY shared by both sexes". Human Genetics. 90 (4): 350–5. S2CID 19470332.
- Vilain E, McElreavey K, Jaubert F, Raymond JP, Richaud F, Fellous M (May 1992). "Familial case with sequence variant in the testis-determining region associated with two sex phenotypes". American Journal of Human Genetics. 50 (5): 1008–11. PMID 1570829.
- Müller J, Schwartz M, Skakkebaek NE (July 1992). "Analysis of the sex-determining region of the Y chromosome (SRY) in sex reversed patients: point-mutation in SRY causing sex-reversion in a 46,XY female". The Journal of Clinical Endocrinology and Metabolism. 75 (1): 331–3. PMID 1619028.
- McElreavey KD, Vilain E, Boucekkine C, Vidaud M, Jaubert F, Richaud F, Fellous M (July 1992). "XY sex reversal associated with a nonsense mutation in SRY". Genomics. 13 (3): 838–40. PMID 1639410.
- Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, Foster JW, Frischauf AM, Lovell-Badge R, Goodfellow PN (July 1990). "A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif". Nature. 346 (6281): 240–4. S2CID 4364032.
- Berkovitz GD, Fechner PY, Zacur HW, Rock JA, Snyder HM, Migeon CJ, Perlman EJ (November 1991). "Clinical and pathologic spectrum of 46,XY gonadal dysgenesis: its relevance to the understanding of sex differentiation". Medicine. 70 (6): 375–83. S2CID 37972412.
- Berta P, Hawkins JR, Sinclair AH, Taylor A, Griffiths BL, Goodfellow PN, Fellous M (November 1990). "Genetic evidence equating SRY and the testis-determining factor". Nature. 348 (6300): 448–50. S2CID 3336314.
- Jäger RJ, Anvret M, Hall K, Scherer G (November 1990). "A human XY female with a frame shift mutation in the candidate testis-determining gene SRY". Nature. 348 (6300): 452–4. S2CID 4326539.
- Ellis NA, Goodfellow PJ, Pym B, Smith M, Palmer M, Frischauf AM, Goodfellow PN (January 1989). "The pseudoautosomal boundary in man is defined by an Alu repeat sequence inserted on the Y chromosome". Nature. 337 (6202): 81–4. S2CID 2890077.
- Whitfield LS, Hawkins TL, Goodfellow PN, Sulston J (May 1995). "41 kilobases of analyzed sequence from the pseudoautosomal and sex-determining regions of the short arm of the human Y chromosome". Genomics. 27 (2): 306–11. PMID 7557997.
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
- Genes,+sry at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Sex-Determining+Region+Y+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- PDBe-KB provides an overview of all the structure information available in the PDB for Human Sex-determining region Y protein