Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations

Kevin C Knower, Sabine Kelly, Louisa M Ludbrook, Stefan Bagheri-Fam, Helena Sim, Pascal Bernard, Ryohei Sekido, Robin Lovell-Badge, Vincent R Harley

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)
7 Downloads (Pure)


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.

Original languageEnglish
Article numbere17751
Number of pages9
JournalPloS ONE
Issue number3
Publication statusPublished - 11 Mar 2011


  • 46, XY disorders of sex development
  • cell line
  • enhancer elements, genetic
  • humans
  • male
  • mutant proteins
  • mutation
  • organ specificity
  • SOX9 transcription factor
  • sex-determining region Y protein
  • steroidogenic factor 1
  • testis
  • trans-activators
  • up-regulation


Dive into the research topics of 'Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations'. Together they form a unique fingerprint.

Cite this