Up-Regulation of SOX9 in Sex-Determining Region on the Y Chromosome
Up-Regulation of SOX9 in Sex-Determining Region on the Y Chromosome
Background: In mammals, gonadal sex is normally determined by the presence or absence of the Y chromosome gene SRY. After expression of SRY in the sexually indifferent gonad, a number of genes encoding transcription factors and growth factors implicated in testis differentiation start to show male-specific expression. However, in XX males, these genes must be up-regulated in the absence of SRY, but the aetiology of SRY-negative XX maleness remains unclear.
Aim and Methods: We examined the expression of representative gonad marker genes in SRY-negative XX male testes.
Results: RT-PCR and immunohistochemical studies revealed that SOX9, DAX-1, Ad4BP/SF-1, WT-1, GATA-4 and MIS were expressed in testicular tissues of SRY-negative XX males. Expression levels of SOX9 in testes of these patients averaged 1·9-fold higher than in normal XY testes, while expression levels of Ad4BP/SF-1, DAX-1 and MIS were lower in the SRY-negative XX testes than in XY testes. All XX patients were found to carry two copies of the SOX9 gene per diploid genome as do normal XX females and XY males. The XX male patients also carried two copies of the DAX-1 gene as do normal XX females, while normal XY males carry a single DAX-1 gene.
Conclusions: Our data suggest that lesions affecting SOX9 expression are the key factor in sex determination in SRY-negative XX males, and that the decreased expression of Ad4BP/SF-1, DAX-1 and MIS contribute to their clinical features.
The gene sex-determining region on the Y chromosome (SRY) was identified as a candidate for testis-determining factor (TDF).SRY, located near the pseudoautosomal boundary of the Y chromosome, is the only gene needed to establish male development, as shown by a transgenic study in which XX mice carrying the Sry gene developed as males. On the other hand, when mutation is present in SRY, the gonad does not develop into a testis. Thus, it has been established that in most mammals male development is triggered by expression of the SRY gene, which initiates a cascade of gene interactions ultimately leading to formation of the testis from the indifferent foetal gonad.
The 46, XX male condition is characterized by testicular development in subjects who have two X chromosomes but lack a Y chromosome. The incidence of XX males is quite rare, occurring in approximately 1 in 20 000 male births. XX males typically have pure testicular tissue and normal male external genitalia, small azoospermic testes, Wolffian structures (vas deferens, epididymis, seminal vesicle) and no Müllerian structures (uterus, Fallopian tubes, upper vagina). Approximately 10% of 46, XX males have hypospadias and all are infertile because the presence of two X chromosomes ultimately inhibits spermatogenesis.
The pathogenesis and cause of testis formation in 46, XX males remains unclear. Previous studies have demonstrated that 80% of XX males have Y chromosome material, including TDF. In these cases, abnormal interchange between distal parts of the short arms of X and Y chromosomes at the paternal meiosis results in transfer of some Y chromosome material onto an X, so conferring male-determining ability on that X chromosome. However, the development of other XX males lacking SRY cannot yet be explained by this mechanism, suggesting the involvement of other genes affecting gonad sex differentiation. After the discovery of SRY, a set of genes encoding transcription factors including SOX9,DAX-1,Ad4BP/SF-1,WT1 and GATA4, and growth factors including WNT4,FGF9 and RSPO1 have been revealed to be involved in gonad development. However, no studies have been performed to examine the expression of these gonad marker genes in XX males. In this study, we examined the expression of representative gonad marker genes in SRY-negative XX male testes. Together with the clinical characteristics of these patients, our data implicate up-regulation of SOX9 as a primary factor in the aetiology of these SRY-negative XX males.
Summary and Introduction
Summary
Background: In mammals, gonadal sex is normally determined by the presence or absence of the Y chromosome gene SRY. After expression of SRY in the sexually indifferent gonad, a number of genes encoding transcription factors and growth factors implicated in testis differentiation start to show male-specific expression. However, in XX males, these genes must be up-regulated in the absence of SRY, but the aetiology of SRY-negative XX maleness remains unclear.
Aim and Methods: We examined the expression of representative gonad marker genes in SRY-negative XX male testes.
Results: RT-PCR and immunohistochemical studies revealed that SOX9, DAX-1, Ad4BP/SF-1, WT-1, GATA-4 and MIS were expressed in testicular tissues of SRY-negative XX males. Expression levels of SOX9 in testes of these patients averaged 1·9-fold higher than in normal XY testes, while expression levels of Ad4BP/SF-1, DAX-1 and MIS were lower in the SRY-negative XX testes than in XY testes. All XX patients were found to carry two copies of the SOX9 gene per diploid genome as do normal XX females and XY males. The XX male patients also carried two copies of the DAX-1 gene as do normal XX females, while normal XY males carry a single DAX-1 gene.
Conclusions: Our data suggest that lesions affecting SOX9 expression are the key factor in sex determination in SRY-negative XX males, and that the decreased expression of Ad4BP/SF-1, DAX-1 and MIS contribute to their clinical features.
Introduction
The gene sex-determining region on the Y chromosome (SRY) was identified as a candidate for testis-determining factor (TDF).SRY, located near the pseudoautosomal boundary of the Y chromosome, is the only gene needed to establish male development, as shown by a transgenic study in which XX mice carrying the Sry gene developed as males. On the other hand, when mutation is present in SRY, the gonad does not develop into a testis. Thus, it has been established that in most mammals male development is triggered by expression of the SRY gene, which initiates a cascade of gene interactions ultimately leading to formation of the testis from the indifferent foetal gonad.
The 46, XX male condition is characterized by testicular development in subjects who have two X chromosomes but lack a Y chromosome. The incidence of XX males is quite rare, occurring in approximately 1 in 20 000 male births. XX males typically have pure testicular tissue and normal male external genitalia, small azoospermic testes, Wolffian structures (vas deferens, epididymis, seminal vesicle) and no Müllerian structures (uterus, Fallopian tubes, upper vagina). Approximately 10% of 46, XX males have hypospadias and all are infertile because the presence of two X chromosomes ultimately inhibits spermatogenesis.
The pathogenesis and cause of testis formation in 46, XX males remains unclear. Previous studies have demonstrated that 80% of XX males have Y chromosome material, including TDF. In these cases, abnormal interchange between distal parts of the short arms of X and Y chromosomes at the paternal meiosis results in transfer of some Y chromosome material onto an X, so conferring male-determining ability on that X chromosome. However, the development of other XX males lacking SRY cannot yet be explained by this mechanism, suggesting the involvement of other genes affecting gonad sex differentiation. After the discovery of SRY, a set of genes encoding transcription factors including SOX9,DAX-1,Ad4BP/SF-1,WT1 and GATA4, and growth factors including WNT4,FGF9 and RSPO1 have been revealed to be involved in gonad development. However, no studies have been performed to examine the expression of these gonad marker genes in XX males. In this study, we examined the expression of representative gonad marker genes in SRY-negative XX male testes. Together with the clinical characteristics of these patients, our data implicate up-regulation of SOX9 as a primary factor in the aetiology of these SRY-negative XX males.
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