文部科学省科学研究費特定領域研究「性分化機構の解明」 *

研究成果

諸橋 憲一郎 MOROHASHI, Ken-ichirou
基礎生物学研究所 性差生物学研究部門
研究項目A03 「性分化異常症の解析」
研究課題 性分化を制御する遺伝子カスケードの解明

Mesonephric FGF signaling is associated with the development of sexually indifferent gonadal primordium in chick embryos. Hidefumi Yoshioka, Yoshiyasu Ishimaru, Noriyuki Sugiyama, Naoki Tsunekawa, Toshiaki Noce, Megumi Kasahara, and Ken-ichirou Morohashi Dev. Biol. 280, 150-161, 2005

研究内容概説ーFGF9はマウスにおいては生殖腺の雄化に不可欠な因子であることが分かっている。本研究ではニワトリ生殖腺におけるFGF9の機能を解析した。ニワトリ胚ではFGF9はAd4BP/SF-1やDMRT1陽性の生殖腺原基に接して発現し、生殖腺原基にはFGF受容体が発現することが分かった。そこで予定生殖腺を含む領域にFGF9を強制発現させたところ、細胞増殖の亢進を引き起こし、結果的に生殖腺の異常な増殖が認められた。これらの細胞は生殖腺マーカーを発現すること、また始源生殖細胞がその周囲に集まることから、生殖腺としての特徴を有していると思われた。しかしながら、強制発現したFGF9が雄のマーカー遺伝子の発現を誘導することはなかった。この結果は、ニワトリとマウスにおけるFGF9の機能は異なること、またはFGF9が生殖腺の形成と雄化に関与するが、本研究におけるFGF9の強制発現は生殖腺形成機能を増強したことなどが考えられる。本研究は兵庫教育大学の吉岡秀文先生との共同研究である。

Small Ubiquitin-Like Modifier 1 (SUMO-1) Modification of the Synergistic Control Motif of Ad4 Binding Protein/Steroidogenic Factor 1 (Ad4BP/SF-1) Regulates Synergistic Transcription between Ad4BP/SF-1 and Sox9. Komatsu T, Mizusaki H, Mukai T, Ogawa H, Baba D, Shirakawa M, Hatakeyama S, Nakayama K, Yamamoto H, Kikuchi A, Morohashi K. Mol Endocrinol, 18, 2451-2462, 2004

研究内容概説ーAd4BP/SF-1は、生殖腺の形成と機能に必須な転写因子である。本論文では、Ad4BP/SF-1の新たな活性調節機構として、タンパク質の翻訳後修飾の一つであるSUMO化の存在を示した。Ad4BP/SF-1にはSUMO化を受ける2つのリジン残基が存在し、1つは協調的な転写活性化を抑制するSynergy Control Motif と呼ばれる領域内に存在した。雄胎児生殖腺の形成に重要なミュラー管阻害因子の発現は、Ad4BP/SF-1とSox9の協調的な転写活性化により制御されることが知られている。本論文において、Ad4BP/SF-1とSox9両者はSUMO化されることが示され、さらにSUMO化により両者の協調的な転写活性化が抑制されるメカニズムの存在が示唆された。(本論文は10月号表紙に選ばれました。)


2007年発表論文

Involvement of aryl hydrocarbon receptor (AhR) in maintenance of seminal vesicle through sexually different target gene expression. Takashi Baba, Yuichi Shima, Junsei Mimura, Motohiko Oshima, Yoshiaki Fujii-Kuriyama, and Ken-ichirou Morohashi Sexual Development in press

Mastermind-like domain containing 1 (MAMLD1 or Cxorf6) transactivates the Hes3 promoter, augments testosterone production, and contains the SF1 target sequence. Maki Fukami, Yuka, Wada, Michiyo Okada, Fumiko Kato, Noriyuki Katsumata, Takashi Baba, Ken-ichirou Morohashi, Jocelyn Laporte, Motoo Kitagawa, and Tsutomu Ogata J. Biol. Chem. In press

Importance of forkhead transcription factor Fkhl18 for development of testicular vasculature. Yuko Sato, Takashi Baba, Mohamad Zubair, Kanako Miyabayashi, Yoshiro Toyama, Mamiko Maekawa, Akiko Owaki, Hirofumi Mizusaki1, Tatsuya Sawamura, Kiyotaka Toshimori, Ken-ichirou Morohashi, and Yuko Katoh-Fukui Mol. Repro. Dev. In press

Mechanism of asymmetric ovarian development in birds. Yoshiyasu Ishimaru, Tomoko Komatsu, Megumi Kasahara, Yuko Katoh-Fukui, Yoshiro Toyama, Mamiko Maekawa, Kiyotaka Toshimori, Roshantha A. S. Chandraratna, Ken-ichirou Morohashi, and Hidefumi Yoshioka (*; The last two authors equally contributed to this work.) Development in press

Clinical and molecular analyses of SRY-negative XX male patients -Correlation between clinical findings and expression of transcription factors implicated in gonadal sex differentiation- Yoshiyuki Kojima, Yutaro Hayashi, Shoichi Sasaki, Peter Koopman, Ken-ichirou Morohashi, and Kenjiro Kohri Clin. Endocrinol. In press

Germ cells are essential for sexual dimorphism in the medaka gonad. Hiromi Kurokawa, Daisuke Saito, Yuko Katoh-Fukui, Kohei Ohta, Takashi Baba, Ken-ichirou Morohashi, and Minoru Tanaka Pro. Natl. Acad. Sci. USA 104, 16958-16963, 2007.

Liver receptor homologue-1 (LRH-1) activates the promoter of brain aromatase (cyp19a2) in a teleost fish, the medaka, Oryzias latipes. Yuki Ohmuro-Matsuyama, Kataaki Okubo, Masaru Matsuda, Shigeho Ijiri, Deshou Wang, Guijun Guan, Taiga Suzuki, Makoto Matsuyama, Ken-ichirou Morohashi, and Yoshitaka Nagahama Mol. Repro. Dev 74, 1065-1071, 2007.

Atrazine-induced aromatase expression is SF-1-dependent: Implications for endocrine disruption in wildlife and reproductive cancers in humans. WuQiang Fan, Toshihiko Yanase, Hidetaka Morinaga, Shigeki Gondo, Taijiro Okabe, Masatoshi Nomura, Tomoko Komatsu, Ken-Ichirou Morohashi, Tyrone B. Hayes, Ryoichi Takayanagi, and Hajime Nawata Environmental Health Perspectives 115, 720-727, 2007

Foxl2 up-regulates aromatase gene transcription in a female-specific manner by binding to the promoter as well as interacting with Ad4BP/SF-1. De-Shou Wang, Tohru Kobayashi, Lin-Yan Shou, Yuki Ohmuro-Matsuyama, Gui-Jun Guan, Shigeho Ijiri, Funie Sakai, Masaru Matsuda, Yasushi Shibata, Kataaki Okubo, Ken-chirou Morohashi, and Yoshitaka Nagahama Mol. Endocrinol. 21, 712-725, 2007

Hypogonadotropic hypogonadism in an adult female with a heterozygous hypomorphic mutation of SOX2. Naoko Sato, Yusuke Kamachi, Hisato Kondoh, Yuichi Shima, Ken-ichirou Morohashi, Reiko Horikawa and Tsutomu Ogata Eur. J. Endocrinol. 156, 169-173, 2007

2006年発表論文

CXorf6 is a causative gene for hypospadias. Maki Fukami, Yuka Wada, Kanako Miyabayashi, Ichizo Nishino, Tomonobu Hasegawa, Giovanna Camerino, Christine Kretz, Anna Buj-Bello, Jocelyn Laporte, Gen Yamada,Ken-ichirou Morohashi, and Tsutomu Ogata?Nature Genetics 38, 1369-1371, 2006

Role of transcription factors Ad4BP/SF-1 and DAX-1 in steroidogenesis and spermatogenesis in human testicular development and idiopathic azospermia. Yoshiyuki Kojima, Shoichi Sakaki, Yutaro Hayashi, Yukihiro Umemoto, Ken-ichirou Morohashi, and Kenjiro Kohri Int. J. Urol. 13, 785-793, 2006

Two-step regulation of Ad4BP/SF-1 gene transcription during fetal adrenal development; initiation by a Hox-Pbx1-Prep1 complex and maintenance via autoregulation by Ad4BP/SF-1. M. Zubair, S. Ishihara, S. Oka, K. Okumura, K. Morohashi Mol. Cell. Biol. 26, 4111-4121, 2006

Differential Gene Dosage Effects of Ad4BP/SF-1 on Target Tissue Development. Fatchiyah, M. Zubair, Y. Shima, S. Oka, S. Ishihara, Y. Fukui-Katoh, K. Morohashi Biochem. Biophys. Res. Commun. 341, 1036-1045, 2006

2005年発表論文

Ah (dioxin) receptor as a key factor in the regulation of female reproduction. Takashi Baba, Junsei Mimura, Naohito Nakamura, Nobuhiro Harada, Masayuki Yamamoto, Ken-ichirou Morohashi* and Yoshiaki Fujii-Kuriyama* (*; The last two authors equally contributed to this work.) Mol. Cell. Biol. 25, 10040-10051, 2005

VMH specific enhancer of Ad4BP/SF-1 gene. Yuichi Shima, Mohamad Zubair, Satoru Ishihara, Yuko Shinohara, Sanae Oka, Shioko Kimura, Sachiyo Suita, and Ken-ichirou Morohashi Mol. Endocrinol. 19, 2812-2823, 2005

Kamei Y, Aoyama Y, Fujimoto T, Kenmotsu N, Kishi C, Koushi M, Sugano S, Morohashi K, Kamiyama R, Asakai R. A steroidogenic cell line with differentiation potential from mouse granulosa cells, transfected with Ad4BP and SV40 large T antigen genes. J. Endocrinol. 185, 187-195, 2005

Yuko Katoh-Fukui, Akiko Owaki, Yoshirou Sotoyama, Masatomo Kusaka, Yuko Shinohara, Mamiko Maekawa, Kiyotaka Toshimori, and Ken-ichirou Morohashi Mouse Polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF-1 expression. Blood.106 ,1612-1620,2005

Makoto Matsuyama, Hirofumi Mizusaki, Akihiko Shimono, Tokuo Mukai, Katsuzumi Okumura, Kuniya Abe, Kiyoshi Shimada, and Ken-ichirou Morohashi Novel Isoform of Vinexin, Vinexin Regulates Sox9 Gene Expression through activating MAPK Cascade in Mouse Fetal Gonad. Genes to Cells 10, 421-434, 2005

Hidefumi Yoshioka, Yoshiyasu Ishimaru, Noriyuki Sugiyama, Naoki Tsunekawa, Toshiaki Noce, Megumi Kasahara, and Ken-ichirou Morohashi Mesonephric FGF signaling is associated with the development of sexually indifferent gonadal primordium in chick embryos. Dev. Biol. 280, 150-161, 2005

Satoru Ishihara and Ken-ichirou Morohashi Identification of the boundary for histone acetylation between nuclear receptor genes, Ad4BP/SF-1 and GCNF, aligned in tandem. Biochem. Biophys. Res. Commun. 329, 554-562, 2005

Katsumi Toda, Yoshihiro Hayashi, Teruhiko Okada, Ken-ichirou Morohashi, and Toshiji Saibara Expression of the estrogen-inducible EGFP gene in aromatase-deficient mice reveals differential tissue-response to estrogenic compounds. Mol. Cell. Endocrinol. 229, 119-126, 2005

2004年発表論文

Tomonobu Hasegawa, Maki Fukami, Naoko Sato, Goro Sasaki, Keiko Fukutani, Ken-ichirou Morohashi, and Tsutomu Ogata Testicular Dysgenesis without Adrenal Insufficiency in a 46,XY Patient with a Heterozygous Inactive Mutation of Steroidogenic Factor-1. J. Clin. Endocrinol. Metab. 89, 5930-5935, 2004

Tomoko Komatsu, Hirofumi Mizusaki, Tokuo Mukai, Hidesato Ogawa, Daichi Baba, Masahiro Shirakawa, Shigetsugu Hatakeyama, Kei-ichi Nakayama, Hideki Yamamoto, Akira Kikuchi, and Ken-ichirou Morohashi SUMO-1 Modification of the Synergy Control Motif of Ad4BP/SF-1 Regulates Synergistic Transcription between Ad4BP/SF-1 and Sox9. Mol. Endocrinol. 18, 2451-2462, 2004

Hidesato Ogawa, Ruth T. Yu, Tokuko Haraguchi, Yasushi Hiraoka, Yoshihiro Nakatani, Ken-ichirou Morohashi and Kazuhiko Umesono Nuclear structure-associated TIF2 interacts with glucocorticoid receptor and its target DNA. Biochem. Biophys. Res Commun. 320, 218-225, 2004