Altered SOX9 genital tubercle enhancer region in hypospadias.
Identifieur interne : 001208 ( Main/Exploration ); précédent : 001207; suivant : 001209Altered SOX9 genital tubercle enhancer region in hypospadias.
Auteurs : Rajini Sreenivasan [Australie] ; Christopher T. Gordon [France] ; Sabina Benko [France] ; Robb De Iongh [Australie] ; Stefan Bagheri-Fam [Australie] ; Stanislas Lyonnet [France] ; Vincent Harley [Australie]Source :
- The Journal of steroid biochemistry and molecular biology [ 1879-1220 ] ; 2017.
Descripteurs français
- KwdFr :
- MESH :
English descriptors
- KwdEn :
- MESH :
- chemical , genetics : SOX9 Transcription Factor.
- genetics : Hypospadias, Regulatory Sequences, Nucleic Acid.
- Animals, Cell Line, Female, Genitalia, Female, Genotype, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mutation.
Abstract
Human mutations in the SOX9 gene or its regulatory region can disrupt testicular development, leading to disorders of sex development (DSDs). Our previous work involving the genomic analysis of isolated DSD patients revealed a 78kb minimal sex determining region (RevSex) far upstream of SOX9 that was duplicated in 46,XX and deleted in 46,XY DSDs. It was postulated that RevSex contains a gonadal enhancer. However, the most highly conserved sub-region within RevSex, called SR4, was neither responsive to sex determining factors in vitro nor active in the gonads of transgenic mice, suggesting that SR4 may not be functioning as a testicular enhancer. Interestingly, SR4 transgenic mice showed reporter activity in the genital tubercle, the primordium of the penis and clitoris, a previously unreported domain of Sox9 expression. SOX9 protein was detected in the genital tubercle, notably in the urethral plate epithelium, preputial glands, ventral surface ectoderm and corpus cavernosa. SR4 may therefore function as a Sox9 genital tubercle enhancer, mutations of which could possibly lead to hypospadias, a birth defect seen in the DSD patients in the RevSex study. SR4 activity and the observed SOX9 expression pattern suggest that SR4 may function as a Sox9 genital tubercle enhancer. However, conditional ablation of Sox9 in the genital tubercle using Shh-Cre/+;Sox9(flox/flox) mice revealed no genital tubercle abnormalities, possibly due to compensation by similar Sox factors. To conclude, we have identified a novel regulatory enhancer driving Sox9 expression during external genitalia development.
DOI: 10.1016/j.jsbmb.2016.10.009
PubMed: 27989796
Affiliations:
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Gordon</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Embryology and Genetics of Congenital Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Institut Imagine, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Embryology and Genetics of Congenital Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Institut Imagine, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Benko, Sabina" sort="Benko, Sabina" uniqKey="Benko S" first="Sabina" last="Benko">Sabina Benko</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Embryology and Genetics of Congenital Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Institut Imagine, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Embryology and Genetics of Congenital Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Institut Imagine, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="De Iongh, Robb" sort="De Iongh, Robb" uniqKey="De Iongh R" first="Robb" last="De Iongh">Robb De Iongh</name><affiliation wicri:level="4"><nlm:affiliation>Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria</wicri:regionArea><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Bagheri Fam, Stefan" sort="Bagheri Fam, Stefan" uniqKey="Bagheri Fam S" first="Stefan" last="Bagheri-Fam">Stefan Bagheri-Fam</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Genetics and Development, Hudson Institute of Medical Research, Melbourne, Victoria, Australia; Monash University, Melbourne, Victoria, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Molecular Genetics and Development, Hudson Institute of Medical Research, Melbourne, Victoria, Australia; Monash University, Melbourne, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Lyonnet, Stanislas" sort="Lyonnet, Stanislas" uniqKey="Lyonnet S" first="Stanislas" last="Lyonnet">Stanislas Lyonnet</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Embryology and Genetics of Congenital Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Institut Imagine, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Embryology and Genetics of Congenital Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Institut Imagine, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Harley, Vincent" sort="Harley, Vincent" uniqKey="Harley V" first="Vincent" last="Harley">Vincent Harley</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Genetics and Development, Hudson Institute of Medical Research, Melbourne, Victoria, Australia; Monash University, Melbourne, Victoria, Australia. Electronic address: vincent.harley@hudson.org.au.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Molecular Genetics and Development, Hudson Institute of Medical Research, Melbourne, Victoria, Australia; Monash University, Melbourne, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author></analytic><series><title level="j">The Journal of steroid biochemistry and molecular biology</title><idno type="eISSN">1879-1220</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Cell Line</term><term>Female</term><term>Genitalia, Female</term><term>Genotype</term><term>Humans</term><term>Hypospadias (genetics)</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Knockout</term><term>Mice, Transgenic</term><term>Mutation</term><term>Regulatory Sequences, Nucleic Acid (genetics)</term><term>SOX9 Transcription Factor (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Facteur de transcription SOX-9 (génétique)</term><term>Femelle</term><term>Génotype</term><term>Humains</term><term>Hypospadias (génétique)</term><term>Lignée cellulaire</term><term>Mutation</term><term>Mâle</term><term>Souris</term><term>Souris de lignée C57BL</term><term>Souris knockout</term><term>Souris transgéniques</term><term>Système génital de la femme</term><term>Séquences d'acides nucléiques régulatrices (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>SOX9 Transcription Factor</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Hypospadias</term><term>Regulatory Sequences, Nucleic Acid</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Facteur de transcription SOX-9</term><term>Hypospadias</term><term>Séquences d'acides nucléiques régulatrices</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line</term><term>Female</term><term>Genitalia, Female</term><term>Genotype</term><term>Humans</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Knockout</term><term>Mice, Transgenic</term><term>Mutation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Femelle</term><term>Génotype</term><term>Humains</term><term>Lignée cellulaire</term><term>Mutation</term><term>Mâle</term><term>Souris</term><term>Souris de lignée C57BL</term><term>Souris knockout</term><term>Souris transgéniques</term><term>Système génital de la femme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Human mutations in the SOX9 gene or its regulatory region can disrupt testicular development, leading to disorders of sex development (DSDs). Our previous work involving the genomic analysis of isolated DSD patients revealed a 78kb minimal sex determining region (RevSex) far upstream of SOX9 that was duplicated in 46,XX and deleted in 46,XY DSDs. It was postulated that RevSex contains a gonadal enhancer. However, the most highly conserved sub-region within RevSex, called SR4, was neither responsive to sex determining factors in vitro nor active in the gonads of transgenic mice, suggesting that SR4 may not be functioning as a testicular enhancer. Interestingly, SR4 transgenic mice showed reporter activity in the genital tubercle, the primordium of the penis and clitoris, a previously unreported domain of Sox9 expression. SOX9 protein was detected in the genital tubercle, notably in the urethral plate epithelium, preputial glands, ventral surface ectoderm and corpus cavernosa. SR4 may therefore function as a Sox9 genital tubercle enhancer, mutations of which could possibly lead to hypospadias, a birth defect seen in the DSD patients in the RevSex study. SR4 activity and the observed SOX9 expression pattern suggest that SR4 may function as a Sox9 genital tubercle enhancer. However, conditional ablation of Sox9 in the genital tubercle using Shh-Cre/+;Sox9(flox/flox) mice revealed no genital tubercle abnormalities, possibly due to compensation by similar Sox factors. To conclude, we have identified a novel regulatory enhancer driving Sox9 expression during external genitalia development.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li></country><region><li>Victoria (État)</li><li>Île-de-France</li></region><settlement><li>Melbourne</li><li>Paris</li></settlement><orgName><li>Université de Melbourne</li></orgName></list><tree><country name="Australie"><region name="Victoria (État)"><name sortKey="Sreenivasan, Rajini" sort="Sreenivasan, Rajini" uniqKey="Sreenivasan R" first="Rajini" last="Sreenivasan">Rajini Sreenivasan</name></region><name sortKey="Bagheri Fam, Stefan" sort="Bagheri Fam, Stefan" uniqKey="Bagheri Fam S" first="Stefan" last="Bagheri-Fam">Stefan Bagheri-Fam</name><name sortKey="De Iongh, Robb" sort="De Iongh, Robb" uniqKey="De Iongh R" first="Robb" last="De Iongh">Robb De Iongh</name><name sortKey="Harley, Vincent" sort="Harley, Vincent" uniqKey="Harley V" first="Vincent" last="Harley">Vincent Harley</name></country><country name="France"><region name="Île-de-France"><name sortKey="Gordon, Christopher T" sort="Gordon, Christopher T" uniqKey="Gordon C" first="Christopher T" last="Gordon">Christopher T. Gordon</name></region><name sortKey="Benko, Sabina" sort="Benko, Sabina" uniqKey="Benko S" first="Sabina" last="Benko">Sabina Benko</name><name sortKey="Lyonnet, Stanislas" sort="Lyonnet, Stanislas" uniqKey="Lyonnet S" first="Stanislas" last="Lyonnet">Stanislas Lyonnet</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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