Mutations in the SRY gene account for between fifteen to twenty percent of cases of Swyers syndrome. This state often results from improper crossing over between X and Y chromosomes during meiosis in the father, resulting in the presence of SRY gene sequences in X chromosomes.
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Among the molecules described above, much attention has focused on WT1 as a potential regulator of Sry. In summary, the precise regulation of both the levels and onset of Sry expression is important for Sertoli cell differentiation and hence for testis development.
The mechanistic details of how this regulation is achieved, however, remain unknown. After the discovery of Sry , attention turned to the issue of whether it might directly upregulate the male sex-determining pathway, or repress a repressor of that pathway see Box 2. Much of this work focused on the relationship between Sry and Sox9 , another important and early-acting gene that is expressed in Sertoli cells.
In particular, studies have aimed to address whether SRY might regulate Sox9 expression directly or indirectly, and whether Sox9 might be just one of many targets of SRY. Sox9 , which encodes another member of the SOX transcription factor family, is expressed in several developing vertebrate organ systems, including the skeleton, heart, kidneys and brain Wright et al.
In XY mouse gonads, Sox9 expression is upregulated in pre-Sertoli cells immediately after the onset of Sry gene expression, and mimics the wave-like pattern of Sry expression Kent et al. However, unlike Sry in mice, Sox9 expression persists in the gonad beyond The importance of SOX9 for sex determination was revealed when heterozygous human SOX9 mutations were found to be associated with a skeletal deformity syndrome: campomelic dysplasia CD Foster et al.
These observations indicated that SOX9 is sufficient and necessary for testis determination, a conclusion confirmed by the sex reversal phenotype of XY Sox9 -null Chaboissier et al. Consistent with the role of SOX9 as a testis-determining factor, several genes that have a crucial role in testicular development, such as Amh and Pgds , have been identified as direct targets of SOX9 De Santa Barbara et al.
Unlike Sry, Sox9 is conserved among non-mammalian vertebrate species. Despite being long suspected, it took over a decade to prove that SRY sex-determining region on the chromosome Y regulates Sox9 SRY box containing gene 9 directly.
Why did it take so long? Sry has some peculiar features that make it particularly difficult to work with. The non-HMG domain sequence of mouse Sry gene does not have obvious functional domains and is poorly conserved between species.
As a result, it was not known whether SRY acts as a transcriptional activator or a repressor, or even as an architectural factor that acts by changing DNA structure. The fact that SRY binds to a short seven-base target sequence that occurs frequently in the genome made it difficult to identify potential target genes bioinformatically. Furthermore, a lack of suitable cell lines and antibodies hampered molecular approaches. Useful and specific antibodies to SRY now exist, although cell lines remain a problem, as cells typically lose SRY expression after a few passages in culture.
Nor has it been easy to work backwards from Sox9 to find out what regulates its expression, or whether SRY is involved. Translocations and deletions affecting Sox9 function indicate that regulatory elements exist 1 Mb or more upstream of this gene in mice and humans Bishop et al. Therefore, the role of SOX9 in sex determination is considered to be ancestral and pivotal among vertebrates.
Furthermore, because the phenotype of Sox9 overexpression in mouse XX gonads recapitulates that of Sry overexpression, Sox9 is thought to be the only gene that is required downstream of Sry to activate the remainder of the testis-determining programme.
How does SRY upregulate Sox9 expression? TESCO is a 1. SRY and SF1 steroidogenic factor 1 , an orphan nuclear receptor that regulates many genes involved in the differentiation of gonadal and adrenal cells, were found to cooperatively upregulate mouse Sox9 by directly binding to TESCO Sekido and Lovell-Badge, Fig. This positive feedback loop is important not only to maintain Sox9 expression after Sry subsides in mice, but also to ensure that the SRY signal is captured and amplified in each developing Sertoli cell.
Fgf9 has not been proven to be a target of SOX9, but is known to be necessary for the maintenance of Sox9 expression. Furthermore, a centre-to-pole diffusion of FGF9 appears to be essential for proper testicular development in the polar extremities of male mouse gonads, because polar fragments of mouse foetal XY genital ridges cultured separately from central fragments did not maintain Sox9 expression or form testis cords Hiramatsu et al.
Cellular mechanism of SRY function. A schematic of the cellular mechanisms of SRY action. Thus, at least three mechanisms are used to ensure the continued expression of Sox9 and to recruit gonadal somatic cells to the Sox9 -positive Sertoli cell population: cell-autonomous Sox9. In mice, Sry sex-determining region on the chromosome Y is not only expressed in developing gonads, but also in the brain. It is tempting to hypothesise that SRY has some direct role in brain sex determination.
However, the physiological significance of these pathways and the regulatory mechanisms of Sry in the brain have yet to be elucidated. Because so little is known about sex-specific brain differentiation, and because the topic itself is fraught with controversy, it is a challenging task to prove that SRY has a direct role.
These regulatory loops induce the activation of other downstream male pathway events, such as Amh expression, cell proliferation in the coelomic epithelium see Glossary, Box 1 , cell migration from the mesonephros see Glossary, Box 1 and testis-specific glycogenesis Martineau et al.
Other than Sox9 , few SRY target molecules in gonads have been reported. Cbln4 encodes a transmembrane protein and is expressed in a male-specific manner. However, the function of Cbln4 product in testicular development is not known. In summary, the only clear direct target of SRY during testis determination is Sox9 , and so understanding the role of SRY in engaging the testis-determining pathway becomes an issue of studying the molecular roles of SOX9.
Interestingly, in mice, Sry is also expressed in the brain, where other potential targets of its protein have been identified see Box 3 ; these targets are brain specific and so are not relevant to gonadal development. Despite its dramatic biological role, Sry is a fragile and partly debilitated gene. The structure and regulatory sequences of Sry may have been degraded because of its location on the rapidly degrading Y chromosome see Box 4. To respond to the weak Sry expression signal and to establish the male pathway efficiently, Sox9 , apparently the only meaningful target of SRY, has acquired support mechanisms for its own regulation, in the form of cell-autonomous and intercellular signalling-based positive-feedback loops.
Thus, SRY provides the trigger for male sex determination,. Sry sex-determining region on the chromosome Y determines the sexual fate of the organism, but also the fate of the Y chromosome itself. Gene-mapping analysis suggests that the X and Y chromosomes evolved from a pair of identical chromosomes Graves, that began to differentiate when one copy of Sox3 SRY box containing gene 3 acquired a new function in male sex determination.
The chromosome carrying this new gene, Sry , became the Y chromosome. The ancestral Sox3 , the role of which is largely restricted to brain development, resides on what has become the X chromosome.
Having established a new Y chromosome, subsequent selection favoured restricted recombination with the new X, so that Y genes would stay on the Y chromosome. Erosion of the Y chromosome is reflected in the accumulation of Sry mutations, explaining the high level of sequence divergence between mammalian species and perhaps accounting for its relatively low expression levels in mice. Not surprisingly, the use of Sry as a testis-determining trigger seems to have been lost altogether in some species, such as the mole voles Ellobius lutescens and E.
The sex chromosomes in these species are XO or XX; no Y chromosome or any trace of Sry are present, suggesting the existence of a completely new sex-determining system. At the same time, SOX9 provides a means of blocking the pathway of gene activity that leads to the differentiation of ovarian cells, but the mechanism by which it does so remains unclear.
Given the importance of correct Sry regulation, as demonstrated in experimental studies, it may be that regulatory mutations in the unidentified enhancer sequences of SRY may be an important contributing factor to human DSDs. Further study is required to test this possibility. Other fundamental questions about this gene and its protein still remain unanswered: what are precise molecular mechanisms of Sry regulation; what are the functions of the non HMG-domain regions of the protein; and what is the physiological significance of its protein interactions?
Recent technical advances, including bioinformatic analysis and the generation of genetically modified mice, will help to answer the remaining questions surrounding the process of mammalian sex determination, and may provide valuable information for the diagnosis and management of human DSDs.
We thank Josephine Bowles and Terje Svingen for critical reading of the manuscript, and Dagmar Wilhelm for supplying the images for Fig. Development, Journal of Cell Science and Journal of Experimental Biology are Transformative Journals, meaning that they gradually increase their share of Open Access research content each year.
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Swyer syndrome. Curr Opin Endocrinol Diabetes Obes. J Mol Biol. Epub Feb 6. Atypical XX male with the SRY gene located at the long arm of chromosome 1 and a 1qter microdeletion. Am J Med Genet A. Structure-function relationships in human testis-determining factor SRY: an aromatic buttress underlies the specific DNA-bending surface of a high mobility group HMG box.
J Biol Chem. Epub Sep Am J Med Sci. Two new novel point mutations localized upstream and downstream of the HMG box region of the SRY gene in three Indian 46,XY females with sex reversal and gonadal tumour formation. Mol Hum Reprod. Epub May
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