The Role of Sonic Hedgehog-Gli2 Pathway in the Masculinization of External Genitalia
During embryogenesis, sexually dimorphic organogenesis is achieved by hormones produced in the gonad. The external genitalia develop from a single primordium, the genital tubercle, and their masculinization processes depend on the androgen signaling. In addition to such hormonal signaling, the invol...
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| Veröffentlicht in: | Endocrinology (Philadelphia) 2011-07, Vol.152 (7), p.2894-2903 |
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| creator | Miyagawa, Shinichi Matsumaru, Daisuke Murashima, Aki Omori, Akiko Satoh, Yoshihiko Haraguchi, Ryuma Motoyama, Jun Iguchi, Taisen Nakagata, Naomi Hui, Chi-chung Yamada, Gen |
| description | During embryogenesis, sexually dimorphic organogenesis is achieved by hormones produced in the gonad. The external genitalia develop from a single primordium, the genital tubercle, and their masculinization processes depend on the androgen signaling. In addition to such hormonal signaling, the involvement of nongonadal and locally produced masculinization factors has been unclear. To elucidate the mechanisms of the sexually dimorphic development of the external genitalia, series of conditional mutant mouse analyses were performed using several mutant alleles, particularly focusing on the role of hedgehog signaling pathway in this manuscript. We demonstrate that hedgehog pathway is indispensable for the establishment of male external genitalia characteristics. Sonic hedgehog is expressed in the urethral plate epithelium, and its signal is mediated through glioblastoma 2 (Gli2) in the mesenchyme. The expression level of the sexually dimorphic genes is decreased in the glioblastoma 2 mutant embryos, suggesting that hedgehog signal is likely to facilitate the masculinization processes by affecting the androgen responsiveness. In addition, a conditional mutation of Sonic hedgehog at the sexual differentiation stage leads to abnormal male external genitalia development. The current study identified hedgehog signaling pathway as a key factor not only for initial development but also for sexually dimorphic development of the external genitalia in coordination with androgen signaling. |
| doi_str_mv | 10.1210/en.2011-0263 |
| format | Article |
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The external genitalia develop from a single primordium, the genital tubercle, and their masculinization processes depend on the androgen signaling. In addition to such hormonal signaling, the involvement of nongonadal and locally produced masculinization factors has been unclear. To elucidate the mechanisms of the sexually dimorphic development of the external genitalia, series of conditional mutant mouse analyses were performed using several mutant alleles, particularly focusing on the role of hedgehog signaling pathway in this manuscript. We demonstrate that hedgehog pathway is indispensable for the establishment of male external genitalia characteristics. Sonic hedgehog is expressed in the urethral plate epithelium, and its signal is mediated through glioblastoma 2 (Gli2) in the mesenchyme. The expression level of the sexually dimorphic genes is decreased in the glioblastoma 2 mutant embryos, suggesting that hedgehog signal is likely to facilitate the masculinization processes by affecting the androgen responsiveness. In addition, a conditional mutation of Sonic hedgehog at the sexual differentiation stage leads to abnormal male external genitalia development. The current study identified hedgehog signaling pathway as a key factor not only for initial development but also for sexually dimorphic development of the external genitalia in coordination with androgen signaling.</description><identifier>ISSN: 0013-7227</identifier><identifier>EISSN: 1945-7170</identifier><identifier>DOI: 10.1210/en.2011-0263</identifier><identifier>PMID: 21586556</identifier><identifier>CODEN: ENDOAO</identifier><language>eng</language><publisher>Chevy Chase, MD: Endocrine Society</publisher><subject>Androgens ; Androgens - pharmacology ; Animals ; Biological and medical sciences ; Conditional mutant ; Developmental stages ; Embryogenesis ; Embryonic growth stage ; Epithelium ; Epithelium - drug effects ; Epithelium - embryology ; Epithelium - metabolism ; Female ; Fundamental and applied biological sciences. Psychology ; Gene Silencing ; Genitalia ; Genitalia, Female - drug effects ; Genitalia, Female - embryology ; Genitalia, Female - metabolism ; Genitalia, Male - drug effects ; Genitalia, Male - embryology ; Genitalia, Male - metabolism ; Glioblastoma ; Glioma ; Hedgehog protein ; Hedgehog Proteins - genetics ; Hedgehog Proteins - metabolism ; Hormones ; Hypospadias - chemically induced ; Hypospadias - embryology ; Hypospadias - metabolism ; Kruppel-Like Transcription Factors - genetics ; Kruppel-Like Transcription Factors - metabolism ; Male ; Males ; Mesenchyme ; Mesoderm - drug effects ; Mesoderm - metabolism ; Mice ; Mice, Knockout ; Mice, Transgenic ; Mutant Proteins - genetics ; Mutant Proteins - metabolism ; Organogenesis ; Reproduction-Development ; Sex Determination Processes ; Sex differentiation ; Sexual dimorphism ; Signal Transduction ; Testosterone Propionate - pharmacology ; Urethra - drug effects ; Urethra - embryology ; Urethra - metabolism ; Vertebrates: endocrinology ; Zinc Finger Protein Gli2</subject><ispartof>Endocrinology (Philadelphia), 2011-07, Vol.152 (7), p.2894-2903</ispartof><rights>Copyright © 2011 by The Endocrine Society</rights><rights>Copyright © 2011 by The Endocrine Society 2011</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c583t-d389593473084c6eafe24d14b99bd90adb74aed3027e271956eaf2fd686dfb043</citedby><cites>FETCH-LOGICAL-c583t-d389593473084c6eafe24d14b99bd90adb74aed3027e271956eaf2fd686dfb043</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24275812$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21586556$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Miyagawa, Shinichi</creatorcontrib><creatorcontrib>Matsumaru, Daisuke</creatorcontrib><creatorcontrib>Murashima, Aki</creatorcontrib><creatorcontrib>Omori, Akiko</creatorcontrib><creatorcontrib>Satoh, Yoshihiko</creatorcontrib><creatorcontrib>Haraguchi, Ryuma</creatorcontrib><creatorcontrib>Motoyama, Jun</creatorcontrib><creatorcontrib>Iguchi, Taisen</creatorcontrib><creatorcontrib>Nakagata, Naomi</creatorcontrib><creatorcontrib>Hui, Chi-chung</creatorcontrib><creatorcontrib>Yamada, Gen</creatorcontrib><title>The Role of Sonic Hedgehog-Gli2 Pathway in the Masculinization of External Genitalia</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><description>During embryogenesis, sexually dimorphic organogenesis is achieved by hormones produced in the gonad. The external genitalia develop from a single primordium, the genital tubercle, and their masculinization processes depend on the androgen signaling. In addition to such hormonal signaling, the involvement of nongonadal and locally produced masculinization factors has been unclear. To elucidate the mechanisms of the sexually dimorphic development of the external genitalia, series of conditional mutant mouse analyses were performed using several mutant alleles, particularly focusing on the role of hedgehog signaling pathway in this manuscript. We demonstrate that hedgehog pathway is indispensable for the establishment of male external genitalia characteristics. Sonic hedgehog is expressed in the urethral plate epithelium, and its signal is mediated through glioblastoma 2 (Gli2) in the mesenchyme. The expression level of the sexually dimorphic genes is decreased in the glioblastoma 2 mutant embryos, suggesting that hedgehog signal is likely to facilitate the masculinization processes by affecting the androgen responsiveness. In addition, a conditional mutation of Sonic hedgehog at the sexual differentiation stage leads to abnormal male external genitalia development. The current study identified hedgehog signaling pathway as a key factor not only for initial development but also for sexually dimorphic development of the external genitalia in coordination with androgen signaling.</description><subject>Androgens</subject><subject>Androgens - pharmacology</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Conditional mutant</subject><subject>Developmental stages</subject><subject>Embryogenesis</subject><subject>Embryonic growth stage</subject><subject>Epithelium</subject><subject>Epithelium - drug effects</subject><subject>Epithelium - embryology</subject><subject>Epithelium - metabolism</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene Silencing</subject><subject>Genitalia</subject><subject>Genitalia, Female - drug effects</subject><subject>Genitalia, Female - embryology</subject><subject>Genitalia, Female - metabolism</subject><subject>Genitalia, Male - drug effects</subject><subject>Genitalia, Male - embryology</subject><subject>Genitalia, Male - metabolism</subject><subject>Glioblastoma</subject><subject>Glioma</subject><subject>Hedgehog protein</subject><subject>Hedgehog Proteins - genetics</subject><subject>Hedgehog Proteins - metabolism</subject><subject>Hormones</subject><subject>Hypospadias - chemically induced</subject><subject>Hypospadias - embryology</subject><subject>Hypospadias - metabolism</subject><subject>Kruppel-Like Transcription Factors - genetics</subject><subject>Kruppel-Like Transcription Factors - metabolism</subject><subject>Male</subject><subject>Males</subject><subject>Mesenchyme</subject><subject>Mesoderm - drug effects</subject><subject>Mesoderm - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Mutant Proteins - genetics</subject><subject>Mutant Proteins - metabolism</subject><subject>Organogenesis</subject><subject>Reproduction-Development</subject><subject>Sex Determination Processes</subject><subject>Sex differentiation</subject><subject>Sexual dimorphism</subject><subject>Signal Transduction</subject><subject>Testosterone Propionate - pharmacology</subject><subject>Urethra - drug effects</subject><subject>Urethra - embryology</subject><subject>Urethra - metabolism</subject><subject>Vertebrates: endocrinology</subject><subject>Zinc Finger Protein Gli2</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp10ctLHDEYAPBQLHW1vXmWASleOprnZOZSKIuuBUWp6zlkJt_sRsZkTWbq469vht1qC3oKIb98T4T2CD4ilOBjcEcUE5JjWrAPaEIqLnJJJN5CE4wJyyWlchvtxHibrpxz9gltUyLKQohigubzJWS_fAeZb7Nr72yTnYFZwNIv8llnaXal--WDfsqsy_pEL3Rshs46-6x769346-Sxh-B0l83A2V53Vn9GH1vdRfiyOXfRzenJfHqWn1_Ofk5_nOeNKFmfG1ZWomJcMlzypgDdAuWG8LqqalNhbWrJNRiGqQQqSSVGQltTlIVpa8zZLvq-jrsa6jswDbg-6E6tgr3T4Ul5bdX_L84u1cL_VowQUeAqBTjYBAj-foDYq1s_jL3ERBgusGRCJvVtrZrgYwzQvmQgWI07UODUuAM17iDx_X-resF_h57A1w1Iw9RdG7RrbHx1nEpREprc4dr5YfVeynyTkq0lOOObYB2sAsT42s2bhf4BUASrww</recordid><startdate>20110701</startdate><enddate>20110701</enddate><creator>Miyagawa, Shinichi</creator><creator>Matsumaru, Daisuke</creator><creator>Murashima, Aki</creator><creator>Omori, Akiko</creator><creator>Satoh, Yoshihiko</creator><creator>Haraguchi, Ryuma</creator><creator>Motoyama, Jun</creator><creator>Iguchi, Taisen</creator><creator>Nakagata, Naomi</creator><creator>Hui, Chi-chung</creator><creator>Yamada, Gen</creator><general>Endocrine Society</general><general>Oxford University Press</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20110701</creationdate><title>The Role of Sonic Hedgehog-Gli2 Pathway in the Masculinization of External Genitalia</title><author>Miyagawa, Shinichi ; Matsumaru, Daisuke ; Murashima, Aki ; Omori, Akiko ; Satoh, Yoshihiko ; Haraguchi, Ryuma ; Motoyama, Jun ; Iguchi, Taisen ; Nakagata, Naomi ; Hui, Chi-chung ; Yamada, Gen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c583t-d389593473084c6eafe24d14b99bd90adb74aed3027e271956eaf2fd686dfb043</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Androgens</topic><topic>Androgens - pharmacology</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Conditional mutant</topic><topic>Developmental stages</topic><topic>Embryogenesis</topic><topic>Embryonic growth stage</topic><topic>Epithelium</topic><topic>Epithelium - drug effects</topic><topic>Epithelium - embryology</topic><topic>Epithelium - metabolism</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene Silencing</topic><topic>Genitalia</topic><topic>Genitalia, Female - drug effects</topic><topic>Genitalia, Female - embryology</topic><topic>Genitalia, Female - metabolism</topic><topic>Genitalia, Male - drug effects</topic><topic>Genitalia, Male - embryology</topic><topic>Genitalia, Male - metabolism</topic><topic>Glioblastoma</topic><topic>Glioma</topic><topic>Hedgehog protein</topic><topic>Hedgehog Proteins - genetics</topic><topic>Hedgehog Proteins - metabolism</topic><topic>Hormones</topic><topic>Hypospadias - chemically induced</topic><topic>Hypospadias - embryology</topic><topic>Hypospadias - metabolism</topic><topic>Kruppel-Like Transcription Factors - genetics</topic><topic>Kruppel-Like Transcription Factors - metabolism</topic><topic>Male</topic><topic>Males</topic><topic>Mesenchyme</topic><topic>Mesoderm - drug effects</topic><topic>Mesoderm - metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Mutant Proteins - genetics</topic><topic>Mutant Proteins - metabolism</topic><topic>Organogenesis</topic><topic>Reproduction-Development</topic><topic>Sex Determination Processes</topic><topic>Sex differentiation</topic><topic>Sexual dimorphism</topic><topic>Signal Transduction</topic><topic>Testosterone Propionate - pharmacology</topic><topic>Urethra - drug effects</topic><topic>Urethra - embryology</topic><topic>Urethra - metabolism</topic><topic>Vertebrates: endocrinology</topic><topic>Zinc Finger Protein Gli2</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Miyagawa, Shinichi</creatorcontrib><creatorcontrib>Matsumaru, Daisuke</creatorcontrib><creatorcontrib>Murashima, Aki</creatorcontrib><creatorcontrib>Omori, Akiko</creatorcontrib><creatorcontrib>Satoh, Yoshihiko</creatorcontrib><creatorcontrib>Haraguchi, Ryuma</creatorcontrib><creatorcontrib>Motoyama, Jun</creatorcontrib><creatorcontrib>Iguchi, Taisen</creatorcontrib><creatorcontrib>Nakagata, Naomi</creatorcontrib><creatorcontrib>Hui, Chi-chung</creatorcontrib><creatorcontrib>Yamada, Gen</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Endocrinology (Philadelphia)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Miyagawa, Shinichi</au><au>Matsumaru, Daisuke</au><au>Murashima, Aki</au><au>Omori, Akiko</au><au>Satoh, Yoshihiko</au><au>Haraguchi, Ryuma</au><au>Motoyama, Jun</au><au>Iguchi, Taisen</au><au>Nakagata, Naomi</au><au>Hui, Chi-chung</au><au>Yamada, Gen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Role of Sonic Hedgehog-Gli2 Pathway in the Masculinization of External Genitalia</atitle><jtitle>Endocrinology (Philadelphia)</jtitle><addtitle>Endocrinology</addtitle><date>2011-07-01</date><risdate>2011</risdate><volume>152</volume><issue>7</issue><spage>2894</spage><epage>2903</epage><pages>2894-2903</pages><issn>0013-7227</issn><eissn>1945-7170</eissn><coden>ENDOAO</coden><abstract>During embryogenesis, sexually dimorphic organogenesis is achieved by hormones produced in the gonad. The external genitalia develop from a single primordium, the genital tubercle, and their masculinization processes depend on the androgen signaling. In addition to such hormonal signaling, the involvement of nongonadal and locally produced masculinization factors has been unclear. To elucidate the mechanisms of the sexually dimorphic development of the external genitalia, series of conditional mutant mouse analyses were performed using several mutant alleles, particularly focusing on the role of hedgehog signaling pathway in this manuscript. We demonstrate that hedgehog pathway is indispensable for the establishment of male external genitalia characteristics. Sonic hedgehog is expressed in the urethral plate epithelium, and its signal is mediated through glioblastoma 2 (Gli2) in the mesenchyme. The expression level of the sexually dimorphic genes is decreased in the glioblastoma 2 mutant embryos, suggesting that hedgehog signal is likely to facilitate the masculinization processes by affecting the androgen responsiveness. In addition, a conditional mutation of Sonic hedgehog at the sexual differentiation stage leads to abnormal male external genitalia development. The current study identified hedgehog signaling pathway as a key factor not only for initial development but also for sexually dimorphic development of the external genitalia in coordination with androgen signaling.</abstract><cop>Chevy Chase, MD</cop><pub>Endocrine Society</pub><pmid>21586556</pmid><doi>10.1210/en.2011-0263</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| source | Journals@Ovid Ovid Autoload; Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Androgens Androgens - pharmacology Animals Biological and medical sciences Conditional mutant Developmental stages Embryogenesis Embryonic growth stage Epithelium Epithelium - drug effects Epithelium - embryology Epithelium - metabolism Female Fundamental and applied biological sciences. Psychology Gene Silencing Genitalia Genitalia, Female - drug effects Genitalia, Female - embryology Genitalia, Female - metabolism Genitalia, Male - drug effects Genitalia, Male - embryology Genitalia, Male - metabolism Glioblastoma Glioma Hedgehog protein Hedgehog Proteins - genetics Hedgehog Proteins - metabolism Hormones Hypospadias - chemically induced Hypospadias - embryology Hypospadias - metabolism Kruppel-Like Transcription Factors - genetics Kruppel-Like Transcription Factors - metabolism Male Males Mesenchyme Mesoderm - drug effects Mesoderm - metabolism Mice Mice, Knockout Mice, Transgenic Mutant Proteins - genetics Mutant Proteins - metabolism Organogenesis Reproduction-Development Sex Determination Processes Sex differentiation Sexual dimorphism Signal Transduction Testosterone Propionate - pharmacology Urethra - drug effects Urethra - embryology Urethra - metabolism Vertebrates: endocrinology Zinc Finger Protein Gli2 |
| title | The Role of Sonic Hedgehog-Gli2 Pathway in the Masculinization of External Genitalia |
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