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

<h4>Background</h4>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 mainte...

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Autores principales:	Kevin C Knower, Sabine Kelly, Louisa M Ludbrook, Stefan Bagheri-Fam, Helena Sim, Pascal Bernard, Ryohei Sekido, Robin Lovell-Badge, Vincent R Harley
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bea90a38f7f8408cb1c98344a5605be2
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spelling	oai:doaj.org-article:bea90a38f7f8408cb1c98344a5605be22021-11-18T06:57:23ZFailure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations.1932-620310.1371/journal.pone.0017751https://doaj.org/article/bea90a38f7f8408cb1c98344a5605be22011-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21412441/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.Kevin C KnowerSabine KellyLouisa M LudbrookStefan Bagheri-FamHelena SimPascal BernardRyohei SekidoRobin Lovell-BadgeVincent R HarleyPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 3, p e17751 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kevin C Knower Sabine Kelly Louisa M Ludbrook Stefan Bagheri-Fam Helena Sim Pascal Bernard Ryohei Sekido Robin Lovell-Badge Vincent R Harley Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations.
description	<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.
format	article
author	Kevin C Knower Sabine Kelly Louisa M Ludbrook Stefan Bagheri-Fam Helena Sim Pascal Bernard Ryohei Sekido Robin Lovell-Badge Vincent R Harley
author_facet	Kevin C Knower Sabine Kelly Louisa M Ludbrook Stefan Bagheri-Fam Helena Sim Pascal Bernard Ryohei Sekido Robin Lovell-Badge Vincent R Harley
author_sort	Kevin C Knower
title	Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations.
title_short	Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations.
title_full	Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations.
title_fullStr	Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations.
title_full_unstemmed	Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations.
title_sort	failure of sox9 regulation in 46xy disorders of sex development with sry, sox9 and sf1 mutations.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/bea90a38f7f8408cb1c98344a5605be2
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Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations.

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