Failure of SOX9 Regulation in 46XY Disorders of Sex Development with SRY, SOX9 and SF1 Mutations
AuthorKnower, KC; Kelly, S; Ludbrook, LM; Bagheri-Fam, S; Sim, H; Bernard, P; Sekido, R; Lovell-Badge, R; Harley, VR
Source TitlePLoS One
PublisherPUBLIC LIBRARY SCIENCE
AffiliationAnatomy and Neuroscience
Document TypeJournal Article
CitationsKnower, K. C., Kelly, S., Ludbrook, L. M., Bagheri-Fam, S., Sim, H., Bernard, P., Sekido, R., Lovell-Badge, R. & Harley, V. R. (2011). Failure of SOX9 Regulation in 46XY Disorders of Sex Development with SRY, SOX9 and SF1 Mutations. PLOS ONE, 6 (3), https://doi.org/10.1371/journal.pone.0017751.
Access StatusOpen Access
BACKGROUND: In 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 FINDINGS: We 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/SIGNIFICANCE: We 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.
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