Molecular mechanisms of masculinization: role of growth factor signaling and androgen regulation

• Project/Area Number: 25860771
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Endocrinology
• Research Institution: Wakayama Medical University
• Principal Investigator: Murashima Aki 和歌山県立医科大学, 先端医学研究所, 特別研究員 (50637105)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: アンドロゲン受容体 / 細胞増殖因子 / ウォルフ管 / 生殖内分泌学 / 遺伝子改変マウス / アンドロゲン / Shh / Fgf / Wnt/b-catenin / ノックアウトマウス

Outline of Final Research Achievements

Wolffian duct (WD) development is one of the most prominent developmental processes which lead to masculinization of the reproductive tract. Androgen is the most important factor to promote masculinization processes including WD elongation. In this study, the functions of several growth factor signaling and molecular mechanisms of androgen regulation were analyzed during WD development. Conditional knockout studies revealed that Sonic hedgehog (Shh) and Fibroblast growth factor (Fgf) signaling pathways play pivotal roles in WD development. In vitro culture system revealed that Wnt signaling regulated WD masculinization. Further analyses revealed that androgen regulates Wnt signaling through the suppression of Wnt antagonist expression. This study demonstrated the function of growth factor signaling in WD development and identified Wnt signaling as a down-stream target of androgen signaling.

Research Products

• [Int'l Joint Research] University of Virginia/Washington University in St. Louis(米国)
• [Journal Article] Investigation of sexual dimorphisms through mouse models and hormone/hormone-disruptor treatments (2016)
  • Author(s): Ipulan LA, Raga D, Suzuki K, Murashima A, Matsumaru D, Cunha G, Yamada G.
  • Journal Title: Differentiation Volume: 印刷中 Issue: 4-5 Pages: 30072-4
  • DOI: 10.1016/j.diff.2015.11.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ウォルフ管上皮特異的β-catenin 遺伝子ノックアウトマウスの示す異所的尿管芽の 病態解析 (2016)
  • Author(s): 﨑田佳嗣, 岡澤-坂井 美佳, 村嶋亜紀, 山田源
  • Journal Title: 和歌山医学 Volume: 67巻2号
  • NAID: 40020888999
  • Peer Reviewed
• [Journal Article] Region-specific regulation of cell proliferation by Fgf receptor signaling during the Wolffian duct development (2015)
  • Author(s): Mika Okazawa, Aki Murashima, Masayo Harada, Naomi Nakagata, Masafumi Noguchi, Mitsuru Morimoto, Tadashi Kimura, David M. Ornitz, Gen Yamada
  • Journal Title: Developmental Biology Volume: 1;400(1) Issue: 1 Pages: 139-147
  • DOI: 10.1016/j.ydbio.2015.01.023
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Understanding normal and abnormal development of the Wolffian/epididymal duct using transgenic mice (2015)
  • Author(s): Murashima A, Xu B, Hinton BT
  • Journal Title: Asian Journal of Andrology Volume: 17(5) Issue: 5 Pages: 749-55
  • DOI: 10.4103/1008-682x.155540
  • Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Systematic stereoscopic analyses for cloacal development: The origin of anorectal malformations. (2015)
  • Author(s): Matsumaru D, Murashima A, Fukushima J, Senda S, Matsushita S, Nakagata N, Miyajima M, Yamada G.
  • Journal Title: Sci Rep. Volume: 10;5 Issue: 1 Pages: 13943-13943
  • DOI: 10.1038/srep13943
  • Peer Reviewed / Open Access
• [Journal Article] Androgens and mammalian male reproductive tract development (2014)
  • Author(s): Aki Murashima, Satoshi Kishigami, Axel Thomson, Gen Yamada
  • Journal Title: Biochimica et Biophysica Acta Volume: 1849(2) Issue: 2 Pages: 163-170
  • DOI: 10.1016/j.bbagrm.2014.05.020
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Midline-derived Shh regulates mesonephric tubule formation through the paraxial mesoderm. (2014)
  • Author(s): Aki Murashima, Hiroki Akita, Mika Okazawa, Satoshi Kishigami, Naomi Nakagata, Ryuichi Nishinakamura and Gen Yamada.
  • Journal Title: Developmental Biology Volume: 1;386(1) Issue: 1 Pages: 216-26
  • DOI: 10.1016/j.ydbio.2013.12.026
  • Peer Reviewed
• [Journal Article] Non-myocytic androgen receptor regulates the sexually dimorphic development of the embryonic bulbocavernosus muscle. (2014)
  • Author(s): Ipulan LA, Suzuki K, Sakamoto Y, Murashima A, Imai Y, Omori A, Nakagata N, Nishinakamura R, Valasek P and Yamada G.
  • Journal Title: Endocrinology Volume: 155(7) Issue: 7 Pages: 2467-79
  • DOI: 10.1210/en.2014-1008
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] The function of growth factor signaling in the developing Wolffian duct and male reproductive tract (2015)
  • Author(s): Aki Murashima, Mika Okazawa, Gen Yamada
  • Organizer: 7th International Symposium on the Biology of Vertebrate Sex Determination
  • Place of Presentation: コナ、ハワイ、米国
  • Year and Date: 2015-04-13 – 2015-04-17
• [Presentation] The functions of growth factor signaling in the developing Wolffian duct and male reproductive tract (2015)
  • Author(s): Aki Murashima, Mika Okazawa and Gen Yamada
  • Organizer: 7th International Symposium on the Biology of Vertebrate Sex Determination
  • Place of Presentation: Kailua-Kona, Hawaii, USA
  • Year and Date: 2015-04-13
  • Int'l Joint Research
• [Presentation] 線維芽細胞増殖因子受容体（FGFR）シグナリングによる領域特異的なウォルフ管上皮細胞増殖の調節について (2014)
  • Author(s): Mika Okazawa, Aki Murashima, Tadashi Kimura, Gen Yamada
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜、神奈川
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] The functions of growth factor signaling in developing Wolffian duct and male reproductive tract (2014)
  • Author(s): Aki Murashima, Mika Okazawa, Gen Yamada
  • Organizer: 6th international conference on the epididymis
  • Place of Presentation: SIBS、上海、中国
  • Year and Date: 2014-10-31 – 2014-11-03
• [Presentation] Midline-derived Shh regulates mesonephric tubule formation through the paraxial mesoderm (2014)
  • Author(s): Aki Murashima, Hiroki Akita, Mika Okazawa, Satoshi Kishigami, Naomi Nakagata, Ryuichi Nishinakamura, Gen Yamada
  • Organizer: 47th Annual Meeting of the JSDB
  • Place of Presentation: ウインク愛知、名古屋
  • Year and Date: 2014-05-27 – 2014-05-30
• [Presentation] Midline-derived Shh regulates mesonephric tubule formation through the paraxial mesoderm (2014)
  • Author(s): 村嶋亜紀
  • Organizer: 第47回日本発生生物学会大会
  • Place of Presentation: ウインクあいち（愛知）
• [Presentation] ウォルフ管雄性化過程と精巣上体上皮分化過程におけるアンドロゲンシグナルの機能解析
  • Author(s): 村嶋亜紀
  • Organizer: 第32回日本アンドロロジー学会
  • Place of Presentation: グランキューブ大阪（大阪）
• [Presentation] 正中構造由来のSonic hedgehogは沿軸中胚葉を介して中腎細管の形成を制御する
  • Author(s): 村嶋亜紀
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸国際展示場（兵庫）