Abstract
BackgroundIn human embryogenesis, loss of SRY (sex determining region on Y), SOX9 (SRY-related HMG box 9) or SF1 (steroidogenic factor 1) function causes disorders of sex development (DSD). A defining event of vertebrate sex determination is male-specific upregulation and maintenance of SOX9 expression in gonadal pre-Sertoli cells, which is preceded by transient SRY expression in mammals. In mice, Sox9 regulation is under the transcriptional control of SRY, SF1 and SOX9 via a conserved testis-specific enhancer of Sox9 (TES). Regulation of SOX9 in human sex determination is however poorly understood.Methodology/Principal FindingsWe show that a human embryonal carcinoma cell line (NT2/D1) can model events in presumptive Sertoli cells that initiate human sex determination. SRY associates with transcriptionally active chromatin in NT2/D1 cells and over-expression increases endogenous SOX9 expression. SRY and SF1 co-operate to activate the human SOX9 homologous TES (hTES), a process dependent on phosphorylated SF1. SOX9 also activates hTES, augmented by SF1, suggesting a mechanism for maintenance of SOX9 expression by auto-regulation. Analysis of mutant SRY, SF1 and SOX9 proteins encoded by thirteen separate 46,XY DSD gonadal dysgenesis individuals reveals a reduced ability to activate hTES.Conclusions/SignificanceWe demonstrate how three human sex-determining factors are likely to function during gonadal development around SOX9 as a hub gene, with different genetic causes of 46,XY DSD due a common failure to upregulate SOX9 transcription.
Highlights
disorders of sex development (DSD) are among the most common genetic diseases in humans referring to a group of congenital conditions in which the development of the chromosomal, gonadal or anatomical sex has been abnormal [1]
It has been proposed that SRY acts in pre-mRNA processing [29], in our study, and in agreement with others [33], Flag-SRY protein does not co-localize with splicing factor SC-35 (Fig. 1C, lower panel)
The key event that defines testis determination is the male-specific upregulation of SOX9
Summary
DSDs are among the most common genetic diseases in humans referring to a group of congenital conditions in which the development of the chromosomal, gonadal or anatomical sex has been abnormal [1]. Mutations in the key testis-determining factor SRY result in 46,XY DSD. The incidence of SRY mutations in 46,XY DSD is quite small (10–15%) and does support the notion that genes other than SRY are essential for proper testis development. Despite the ongoing identification of a number of these key testis-determining genes [4], most of which are transcription factors, the actions, co-factors and downstream targets of human SRY have proven difficult to ascertain. Loss of SRY (sex determining region on Y), SOX9 (SRY-related HMG box 9) or SF1 (steroidogenic factor 1) function causes disorders of sex development (DSD). A defining event of vertebrate sex determination is male-specific upregulation and maintenance of SOX9 expression in gonadal pre-Sertoli cells, which is preceded by transient SRY expression in mammals. Regulation of SOX9 in human sex determination is poorly understood
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