Disease relevance of Sry

• SOX9 enhancement of aggrecan gene promoter activity and SOX9 transactivation through the Sry/Sox consensus sequence were not observed in osteoblastic osteosarcoma cells (ROS17/2.8), indicating the dependence on the cellular background [1].
• However, Leydig cells and a Leydig cell tumor were negative for Sry expression [2].
• Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for human Hirschsprung disease [3].
• Isolation of a novel Sry-related gene that is expressed in high-metastatic K-1735 murine melanoma cells [4].
• Here, we describe a study of Sry detection in the gonads of intersex patients including 5 male pseudohermaphrodite (MPH), 4 XX true hermaphrodite (TH) and each 1 mixed gonadal dysgenesis (MGD) and XX sex reversal, and in the clitoris of 3 female pseudohermaphrodite (FPH) by fluorescent in situ hybridization (FISH) [5].

Psychiatry related information on Sry

• While this result does not prove a direct interaction between the two genes, it defines the critical period during which Sry must act to initiate Sertoli cell differentiation [6].
• To directly test the hypothesis that social behaviors are influenced by differences in sex chromosome complement other than Sry, we used a transgenic mouse model in which gonadal sex and sex chromosome complement are uncoupled [7].
• Sry polymorphisms, as illustrated by the molossinus Sry allele, can serve as molecular markers for studies on the evolution of wild M. musculus populations and can help determine the role sex determination plays in speciation [8].

High impact information on Sry

• Fgf9 appears to act downstream of Sry to stimulate mesenchymal proliferation, mesonephric cell migration, and Sertoli cell differentiation in the embryonic testis [9].
• Here, we show that Sox9 is sufficient to induce testis formation in mice, indicating that it can substitute for the sex-determining gene Sry [10].
• In most mammals, male development is triggered by the transient expression of the Y-chromosome gene, Sry, which initiates a cascade of gene interactions ultimately leading to the formation of a testis from the indifferent fetal gonad [11].
• To test directly whether the glutamine-rich region is required for Sry function in vivo, we created truncation mutations of the Mus musculus musculus Sry gene and tested their ability to induce testis formation in XX embryos using a transgenic mouse assay [12].
• Sry constructs that encode proteins lacking the glutamine-rich region were unable to effect male sex determination, in contrast to their wild-type counterparts [12].

Biological context of Sry

• We also show that the anti-Müllerian hormone gene, which contains a Sry consensus binding element in its 5' promoter region, is not transcribed at this time [13].
• To test whether SOX9 was sufficient to generate a fully fertile male in the absence of Sry, we constructed an XY(Sry(-))Ods/+ male mouse, in which the male phenotype is controlled autosomally by the Ods mutation [14].
• These cells were purified from gonads of male and female transgenic embryos at 10.5 dpc (shortly after Sry transcription is activated) and 11.5 dpc (when Sox9 transcription begins), and their transcriptomes analysed using Affymetrix genome arrays [15].
• This begins in the unique region 5' of the protein coding region and extends several kilobases into the 3' arm of the large inverted repeat which bounds the Sry genomic locus [6].
• This was compared with anti-Müllerian hormone gene expression, an early marker of Sertoli cells and the first known downstream gene of Sry [6].

Anatomical context of Sry

• Transcription of the sex-determining region genes Sry and Zfy in the mouse preimplantation embryo [13].
• In the mouse, Sry is expressed by germ cells in the adult testis and by somatic cells in the genital ridge [6].
• In the absence of Sry, or if Sry is expressed at insufficient levels, the support cell precursors differentiate as granulosa cells, thus initiating the ovarian pathway [16].
• With the aim of identifying the gene(s) located downstream from SRY, we transfected an ES cell line with XX karyotype, TMA-18, with a Sry DNA construct and established cell lines, TS18-1 and TS18-2, where the transfected Sry was expressed in the functional linear mRNA form [17].
• For example, in mice, the Y-linked gene Sry triggers differentiation of Sertoli cells from a cell population originating in the coelomic epithelium overlying the nascent gonad that also gives rise to uncharacterised interstitial cells [18].

Associations of Sry with chemical compounds

• Our data indicate a mechanism whereby Sry uses both a cell-autonomous mechanism and a PGD2-mediated signaling mechanism to stimulate expression of Sox9 and induce the differentiation of Sertoli cells in vivo [19].
• These sex differences are primarily attributed to steroid hormone differences during development and/or adulthood, especially the higher levels of androgens experienced by males, which are caused ultimately by the presence of the testis-determining gene Sry on the Y chromosome [7].
• Bisulfite restriction mapping and sodium bisulfite sequencing revealed that the 5'-flanking region of the Sry gene was hypermethylated in the 8.5-dpc embryos in which the Sry gene was not expressed [20].
• When the transgene was bred into a constitutively male line of mice (Odsex; Bishop et al.: Nat Genet 26:490-494, 2000), autofluorescence was visible in genital ridges of XX animals, in the genetic absence of Sry protein [21].
• Treatment with DEX enhanced Col2a1 mRNA expression in these chondrocytes and furthermore, DEX enhanced the activity of Col2-CAT (chloramphenicol acetyltransferase) construct containing a 1.6 kb intron fragment where chondrocyte-specific Sry/Sox- consensus sequence is located [22].

Regulatory relationships of Sry

• No clear indication of Sry-induced enhancement of Sox9 expression was obtained in the present series of experiments [17].
• This analysis indicated: (1) Sry is first expressed in cells located centrally in the genital ridge and then later in cells located at the cranial and caudal poles, (2) Sry is expressed exclusively in pre-Sertoli cells in the urogenital ridge, and (3) Sertoli and granulosa cells develop from a common precursor [23].

Other interactions of Sry

• Sox9 is sufficient for functional testis development producing fertile male mice in the absence of Sry [14].
• By contrast, Wt1 and Sf1, which are expressed prior to Sry and necessary for gonad development in both sexes, were expressed normally in both types of mutant XY gonads [16].
• This has led to the proposal that Sry evolved from Sox-3 [24].
• We hypothesize that upregulation of Sox9 expression in precursor somatic cells, a process required for their differentiation as Sertoli cells, depends on the coordinated expression of Dax1, Sry and another gene, Tda1 [25].
• Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2 [16].

Analytical, diagnostic and therapeutic context of Sry

• A 1,277-bp fragment of noncoding sequence flanking the sex determining locus (Sry) was PCR amplified, and 1,063 bases were sequenced and compared among 20 M. domesticus and 1 M. spretus [26].
• Quantitative RT-PCR analysis of the patterns of WT1 expression in developing fetal gonads revealed that although both male and female fetal gonads express WT1, male gonads invariably expressed WT1 mRNA at higher levels than female ones after the Sry expression [17].
• Here we used in situ hybridization to study expression of Sry, and the critical downstream gene Sox9, in strains containing different chromosome combinations to investigate the cause of B6-Y(DOM) sex reversal [27].
• In electrophoretic mobility shift assays (EMSA), we demonstrated that the 3.7 kb 5'-upstream DNA stretch of Wt1 containing potential Sry binding sites was capable of forming molecular complexes with nuclear protein(s) from Sry expressing cells but not with those from control non-Sry expressing cells [28].
• After establishing that the transgene was expressed in fetal gonads similarly to endogenous Sry, the spatial and temporal expression of the Sry-EGFP transgene was investigated in developing gonads by using confocal microscopy and immunofluorescent histochemistry [23].

References