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PubMed2006

Sry and the hesitant beginnings of male development.

In mammals, Sry (sex-determining region Y gene) is the master regulator of male sex determination. The discovery of Sry in 1990 was expected to provide the key to unravelling the network of gene regulation underlying testis development. Intriguingly, no target gene of SRY protein has yet been discovered, and the mechanisms by which it mediates its developmental functions are still elusive. What is clear is that instead of the robust gene one might expect as the pillar of male sexual development, Sry function hangs by a thin thread, a situation that has profound biological, medical and evolutionary implications.

Amino Acid Sequence↗
PubMed1997

Ovarian Sertoli-Leydig cell tumor: a SRY gene-independent pathway of pseudomale gonadal differentiation.

Sertoli-Leydig cell tumors (SLCT) are rare sex-cord stromal tumors of the ovary composed of undifferentiated gonadal stromal cells, Leydig cells (LC), and Sertoli cells (SC), with the latter forming structures resembling fetal testicular tubules. The histogenetic basis of morphological male differentiation patterns in females is controversial. Here, we report a SLCT with intermediate differentiation in a 23-year-old woman investigated by light microscopy, immunohistochemistry for intermediate filaments, and sex steroid hormone receptors (SSHR), as well as by polymerase chain reaction (PCR) for the presence of the sex-determining region Y gene (SRY). Our investigation shows that the SCs of SLCT express progesterone and androgen receptors as well as cytokeratins and vimentin. By PCR, SLCT-derived genomic DNA lacked the SRY gene, indicating that the SLCT results from a SRY gene-independent pathway of pseudomale gonadal differentiation. The expression of progesterone receptors (PRs) in the SCs of the SLCT is in contrast to their absence in testicular SCs, but in line with their presence in ovarian granulosa and surface epithelial cells. Thus, our results provide strong evidence for a close histogenetic relationship between the SLCT and the female gonocyte-supporting cell, the granulosa cell (GC).

Adult↗
PubMedDate not supplied

Onset of sex differentiation: dialog between genes and cells.

During the late 1940s, Alfred Jost demonstrated that mammalian sex differentiation begins in fetal testis, producing two factors necessary for the establishment of phenotypic males. Castrated embryos prior to testis differentiation led to phenotypic female differentiation. Jost proposed the existence of a testis-determining factor (TDF), elucidated in 1990 and named SRY for humans and Sry for mice. Thereafter, an increasing list of genes expressed in the genital ridges of mouse embryos at the onset of gonad differentiation has appeared. To date, it is clear that complete understanding of the mechanisms underlying gonadal sex differentiation in mammals requires identification of key cell lineages in which gonadal-specific genes are expressed. Here, a correlation between known gene expression and gonadal morphologic changes is attempted.

Animals↗
PubMed1998

Dax1 antagonizes Sry action in mammalian sex determination.

DAX1, which encodes an unusual member of the nuclear hormone-receptor superfamily, is a gene that may be responsible for a sex-reversal syndrome in humans, referred to as dosage-sensitive sex reversal, in which XY individuals carrying duplications of Xp21, part of the small arm of the X chromosome, develop as females. XY mice carrying extra copies of mouse Dax1 as a transgene show delayed testis development when the gene is expressed at high levels, but do not normally show sex reversal. Complete sex reversal occurs, however, when the transgene is tested against weak alleles of the sex-determining Y-chromosome gene Sry. These results show that DAX1 is largely, if not solely, responsible for dosage-sensitive sex reversal and provide a model for early events in mammalian sex determination, when precise levels and timing of gene expression are critical.

Animals↗
PubMed1998

A gene involved in XY sex reversal is located on chromosome 9, distal to marker D9S1779.

The genetic mechanisms involved in sex differentiation are poorly understood, and progress in identification of the genes involved has been slow. The fortuitous finding of chromosomal rearrangements in association with a sex-reversed phenotype has led to the isolation of SRY and SOX9, both shown to be involved in the sex-determining pathway. In addition, duplications of the X chromosome, deletions of chromosomes 9 and 10, and translocations involving chromosome 17 have been reported to be associated with abnormal testicular differentiation, leading to male-to-female sex reversal in 46,XY individuals. We present the cytogenetic and molecular analyses of four sex-reversed XY females, each with gonadal dysgenesis and other variable malformations, and with terminal deletions of distal chromosome 9p, resulting from unbalanced autosomal translocations. PCR amplification and DNA sequence analysis of SRY revealed no mutations in the high-mobility-group domain (i.e., HMG box) in any of the four patients. Conventional and molecular cytogenetic analyses of metaphase chromosomes from each patient suggest that the smallest region of overlap (SRO) of deletions involves a very small region of distal band 9p24. Loss-of-heterozygosity studies using 17 highly polymorphic microsatellite markers, as well as FISH using YAC clones corresponding to the most distal markers on 9p, showed that the SRO lies distal to marker D9S1779. These results significantly narrow the putative sex-determining gene to the very terminal region of the short arm of chromosome 9.

Child, Preschool↗
PubMed2005

From SRY to SOX9: mammalian testis differentiation.

Sry (sex-determining region on the Y chromosome) is a master gene that initiates testis differentiation of the bipotential indifferent gonad in mammals. In mice, Sry expression is transiently activated in a center-to-pole wave along the anteroposterior (AP) axis of developing XY gonads. Shortly after the onset of Sry activation, Sox9 (Sry-related HMG box-9), a fundamental testis-differentiation gene common to all vertebrates, is also activated in a center-to-pole pattern similar to the initial Sry expression profile. Several male-specific cellular events, such as glycogenesis, coelomic epithelium proliferation, mesonephric migration and vasculogenesis, are induced in XY gonads following the onset of Sry and Sox9 expression. This paper mainly focuses on recent advances in elucidating the regulatory mechanisms of Sry and Sox9 expression and male-specific cellular events immediately downstream of SRY action during the initial phases of testis differentiation.

Animals↗
PubMed2000

SRY protein is expressed in ovotestis and streak gonads from human sex-reversal.

In mammals, a master gene located on the Y chromosome, the testis-determining gene SRY, controls sex determination. SRY protein is expressed in the genital ridge before testis determination, and in the testis it is expressed in Sertoli and germ cells. Completely sex-reversed patients are classified as either 46,XX males or 46,XY females. SRY mutations have been described in only 15% of patients with 46,XY complete or partial gonadal dysgenesis. However, although incomplete or partial sex-reversal affects 46,XX true hermaphrodites, 46,XY gonadal dysgenesis, and 46,XX/46,XY mosaicism, only 15% of the 46,XX true hermaphrodites analyzed have the SRY gene. Here, we demonstrate that the SRY protein is expressed in the tubules of streak gonads and rete testis, indicating that the SRY protein is normally expressed early during testis determination. Based on these results, we propose that some factors downstream from SRY may be mutated in these 46,XY sex-reversal patients. We have also analyzed SRY protein expression in the ovotestis from 46,XX true hermaphrodites and 46,XX/46,XY mosaicism, demonstrating SRY protein expression in both testicular and ovarian portions in these patients. This suggests that the SRY protein does not inhibit ovary development. These results confirm that other factors are needed for complete testis development, in particular, those downstream of the SRY protein.

DNA-Binding Proteins↗
PubMed2000

Monozygotic twins of opposite sex.

Although discordant karyotypes are known in identical twins, cases involving differences in sex phenotype are rare. We studied identical twins with the 46,XY karyotype - a male with mixed gonadal dysgenesis and a female with "pure" gonadal dysgenesis. The testis-determining SRY gene was present in DNA from both twins but no mutations were detected in the SRY conserved motif. Monozygosity was indicated by short tandem repeat polymorphism analysis. These observations could be attributed to (i) mutation and mosaicism involving "downstream" sex-determining loci, (ii) variable penetrance of genes such as DSS/NR0B1, duplication of which can disrupt the male-determining pathway, or (iii) occurrence of cryptic 45,X gonadal cell lines.

Adolescent↗
PubMed2003

Molecular characterization of three gonad cell lines.

To facilitate the study of the regulation and downstream interactions of genes involved in gonad development it is important to have a suitable cell culture model. We therefore aimed to characterize molecularly three different mouse gonad cell lines. TM3 and TM4 cells were originally isolated from prepubertal mouse gonads and were tentatively identified as being of Leydig cell and Sertoli cell origin, respectively, based upon their morphology and hormonal responses. The third line is a conditionally immortalized cell line, derived from 10.5-11.5 days post-coitum (dpc) male gonads of transgenic embryos carrying a temperature-sensitive SV40 large T-antigen. We studied by reverse transcription-polymerase chain reaction (RT-PCR) the expression profiles of a number of genes known to be important for early gonad development. Moreover, we assessed these cell lines for their capacity to induce SOX9 transcription upon expression of SRY, a key molecular event occurring during sex determination. We found that all three cell lines were unable to upregulate SOX9 expression upon transfection of SRY-expression constructs, even though these cells express many of the studied embryonic gonad genes. These observations point to a requirement for SRY cofactors for direct or indirect upregulation of SOX9 expression during testis determination.

Animals↗
PubMed2004

Fgf9 induces proliferation and nuclear localization of FGFR2 in Sertoli precursors during male sex determination.

Recently, we demonstrated that loss of Fgf9 results in a block of testis development and a male to female sex-reversed phenotype; however, the function of Fgf9 in sex determination was unknown. We now show that Fgf9 is necessary for two steps of testis development just downstream of the male sex-determining gene, Sry: (1) for the proliferation of a population of cells that give rise to Sertoli progenitors; and (2) for the nuclear localization of an FGF receptor (FGFR2) in Sertoli cell precursors. The nuclear localization of FGFR2 coincides with the initiation of Sry expression and the nuclear localization of SOX9 during the early differentiation of Sertoli cells and the determination of male fate.

Animals↗
PubMedDate not supplied

Related function of mouse SOX3, SOX9, and SRY HMG domains assayed by male sex determination.

Sox genes encode proteins related to each other, and to the sex determining gene Sry, by the presence of a DNA binding motif known as the HMG domain. Although HMG domains can bind to related DNA sequences, Sox gene products may achieve target gene specificity by binding to preferred target sequences or by interacting with specific partner proteins. To assess their functional similarities, we replaced the HMG box of Sry with the HMG box of Sox3 or Sox9 and tested whether these constructs caused sex reversal in XX mice. Our results indicate that such chimeric transgenes can functionally replace Sry and elicit development of testis cords, male patterns of gene expression, and elaboration of male secondary sexual characteristics. This implies that chimeric SRY proteins with SOX HMG domains can bind to and regulate SRY target genes and that potential SRY partner factor interactions are not disrupted by HMG domain substitutions. genesis 28:111-124, 2000.

Amino Acid Sequence↗