ABSTRACT
During mouse sex determination, SRY upregulates the core testis-specific enhancer of Sox9, TESCO. Mutations in human SRY are found in one third of cases with XY pure gonadal dysgenesis (XY GD; Swyer syndrome), while two thirds remain unexplained. Heterozygous SOX9 mutations can cause XY GD in association with the skeletal malformation syndrome campomelic dysplasia. We hypothesized that human TESCO mutations could cause isolated XY GD. Sixty-six XY GD cases with an intact SRY were analyzed for TESCO point mutations or deletions. No mutations were identified. We conclude that TESCO mutations are not a common cause of XY GD.
Subject(s)
Gonadal Dysgenesis, 46,XY/genetics , Homeodomain Proteins/genetics , Mutation/genetics , Sex-Determining Region Y Protein/genetics , Tumor Suppressor Proteins/genetics , Animals , Cytoskeletal Proteins , Humans , LIM Domain Proteins , Male , Mice , RNA-Binding ProteinsABSTRACT
The study of the mammalian sex-determining pathway has been hampered by the lack of cell culture systems to investigate the underlying molecular relationships between sex-determining genes. Recent approaches using high-throughput genome-wide studies have revealed a number of sexually dimorphic genes expressed in the developing mouse gonad. Here, we investigated a human testicular cell line in terms of its expression of known sex-determining genes and newly identified candidates. The human embryonal carcinoma cell line NT2/D1 was screened for the expression of 46 genes with known or potential roles in the sex-determining and differentiation pathway. Forty genes tested were expressed in NT2/D1 cells including the testis-determining genes SRY, SOX9, SF-1, DHH and FGF9. Genes not expressed included WT1, DAX1 and the ovary-specific genes FOXL2 and WNT4. Cell-specific markers demonstrate that NT2/D1 cells reflect a number of cell types in the gonad including Sertoli, Leydig and germ cells. Our results suggest that male pathways initiated by SRY, SOX9 and SF-1 remain intact in these cells. Lack of expression of ovary-specific genes is consistent with a commitment of these cells to the male lineage. Manipulation of gene expression in this cell line could be an important new in vitro tool for the discovery of new human sex-determining genes.
Subject(s)
Gene Expression Profiling , Urogenital System/metabolism , Carcinoma, Embryonal/genetics , Carcinoma, Embryonal/pathology , Cell Line, Tumor , Female , Gene Expression Regulation, Developmental , Gene Expression Regulation, Neoplastic , Germ Cells/metabolism , Gonads/metabolism , Humans , Leydig Cells/metabolism , Male , Ovary/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sertoli Cells/metabolism , Sex Determination Processes , Sex Differentiation/genetics , Signal Transduction/genetics , Testis/metabolism , Urogenital System/embryologyABSTRACT
The decision of the bi-potential gonad to develop into either a testis or ovary is determined by the presence or absence of the Sex-determining Region gene on the Y chromosome (SRY). Since its discovery, almost 13 years ago, the molecular role that SRY plays in initiating the male sexual development cascade has proven difficult to ascertain. While biochemical studies of clinical mutants and mouse genetic models have helped in our understanding of SRY function, no direct downstream targets of SRY have yet been identified. There are, however, a number of other genes of equal importance in determining sexual phenotype, expressed before and after expression of SRY. Of these, one has proven of central importance to mammals and vertebrates, SOX9. This review describes our current knowledge of SRY and SOX9 structure and function in the light of recent key developments.
