title: Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Molecular Genetics and Development, Prince Henry's Institute, Melbourne, Victoria, Australia. vincent.harley@princehenrys.org
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Knower
authors.forename: Sabine
authors.initials: S
authors.lastname: Kelly
authors.forename: Louisa M
authors.initials: LM
authors.lastname: Ludbrook
authors.forename: Stefan
authors.initials: S
authors.lastname: Bagheri-Fam
authors.forename: Helena
authors.initials: H
authors.lastname: Sim
authors.forename: Pascal
authors.initials: P
authors.lastname: Bernard
authors.forename: Ryohei
authors.initials: R
authors.lastname: Sekido
authors.forename: Robin
authors.initials: R
authors.lastname: Lovell-Badge
authors.forename: Vincent R
authors.initials: VR
authors.lastname: Harley
mesh_terms: D002460:Cell Line; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D006801:Humans; D008297:Male; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D051876:Sex-Determining Region Y Protein / Q000235:genetics*; D054339:Steroidogenic Factor 1 / Q000235:genetics*; D013737:Testis / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D050505:Mutant Proteins; C515057:NR5A1 protein, human; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein; D054339:Steroidogenic Factor 1; D015534:Trans-Activators