Show simple item record

dc.contributor.authorKnower, KC
dc.contributor.authorKelly, S
dc.contributor.authorLudbrook, LM
dc.contributor.authorBagheri-Fam, S
dc.contributor.authorSim, H
dc.contributor.authorBernard, P
dc.contributor.authorSekido, R
dc.contributor.authorLovell-Badge, R
dc.contributor.authorHarley, VR
dc.date.accessioned2020-12-21T03:42:36Z
dc.date.available2020-12-21T03:42:36Z
dc.date.issued2011-03-11
dc.identifier.citationKnower, 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.
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/11343/257320
dc.description.abstractBACKGROUND: 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.
dc.languageEnglish
dc.publisherPUBLIC LIBRARY SCIENCE
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleFailure of SOX9 Regulation in 46XY Disorders of Sex Development with SRY, SOX9 and SF1 Mutations
dc.typeJournal Article
dc.identifier.doi10.1371/journal.pone.0017751
melbourne.affiliation.departmentAnatomy and Neuroscience
melbourne.source.titlePLoS One
melbourne.source.volume6
melbourne.source.issue3
dc.rights.licenseCC BY
melbourne.elementsid1269359
melbourne.contributor.authorHarley, Vincent
melbourne.contributor.authorBagheri-Fam, Stefan
dc.identifier.eissn1932-6203
melbourne.accessrightsOpen Access


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record