2008 Fiscal Year Final Research Report
Elucidation of gene cascade regulating sex differentiation
Project/Area Number |
16086214
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Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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Allocation Type | Single-year Grants |
Review Section |
Biological Sciences
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Research Institution | Kyushu University (2008) National Institute for Basic Biology (2004-2007) |
Principal Investigator |
MOROHASHI Ken-ichirou Kyushu University, 大学院・医学研究院, 教授 (30183114)
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Co-Investigator(Kenkyū-buntansha) |
KATOH-FUKUI Yuko 国立長寿医療センター研究所, 老化制御研究部・分子制御研究室, 室長 (50342639)
OGAWA Hidesato 基礎生物学研究所, 性差生物学研究部門, 助教 (20370132)
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Project Period (FY) |
2004 – 2008
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Keywords | 性分化 / 転写制御 / エンハンサー / 生殖腺 |
Research Abstract |
種々の遺伝子ノックアウトマウスを用い、雌雄の生殖腺(精巣と卵巣)の性分化過程における、Ad4BP/SF-1、Emx2、M33、Fkhl18、AhR、Wnt4、Dax-1、Sox9などの遺伝子の関係の一端を明らかにした。なかでも、ポリコーム複合体の因子であるM33が性決定遺伝子SRYを制御すること、ダイオキシン受容体AhRが卵巣にて女性ホルモン産生酵素であるアロマターゼ遺伝子を制御することなどが明らかになった。また、Ad4BP/SF-1遺伝子の組織特異的エンハンサーに着目し、精巣にて男性ホルモンを産生するライディッヒ細胞や副腎皮質細胞におけるエンハンサー、脳下垂体エンハンサー、視床下部腹内側核エンハンサーなどを同定した。これらのエンハンサーを用い、各種トランスジェニックマウスを作製し、副腎皮質とライディッヒ細胞の系譜を明らかにした。また、胎仔ライディッヒ細胞-GFPマウスを作製し、胎仔精巣にて男性ホルモンを産生する胎仔ライディッヒ細胞を単離することが可能とした。そして、純化した胎仔ライディッヒ細胞にてマイクロアレイ解析とChIP-シークエンス解析を行ってきた。その結果、胎仔ライディッヒ細胞が男性ホルモンを産生するとの従来からの説が否定され、胎仔生殖腺の性差と成獣生殖腺の性差が質的に異なることを明らかにしてきた。これらの知見は今後の性差に主眼を置く研究の基盤を提供するものである。
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[Journal Article] Identification of NR5A1 (SF-1/AD4BP) gene expression modulators by large-scale gain and loss of function studies2008
Author(s)
N. Sakai, H. Terami, S. Suzuki, M. Haga, K. Nomoto, N. Tsuchida, K. Morohashi, N. Saito, M. Asada, M. Hashimoto, D. Harada, H. Asahara, T. Ishikawa, F. Shimada, K. Sakurada
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Journal Title
J. Endocrinol 198
Pages: 489-497
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[Journal Article] Importance of forkhead transcription factor Fkhl18 for development of testicular vasculature2008
Author(s)
Y. Sato, T. Baba, M. Zubair, K. Miyabayashi, Y. Toyama, M. Maekawa, A. Owaki, H. Mizusaki1, T. Sawamura, K. Toshimori, K. Morohashi, Y. Katoh-Fukui
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Journal Title
Mol. Repro. Dev. 75
Pages: 1361-1371
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[Journal Article] Mastermind-like domain containing 1 (MAMLD1 or Cxorf6) transactivates the Hes3 promoter, augments testosterone production, and contains the SF1 target sequence2008
Author(s)
M. Fukami, Y. Wada, M. Okada, F. Kato, N. Katsumata, T. Baba, K. Morohashi, J. Laporte, M. Kitagawa, T. Ogata
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Journal Title
J. Biol. Chem. 283
Pages: 5525-5532
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[Journal Article] Liver receptor homologue-1 (LRH-1) activates the promoter of brain aromatase (Cyp19a2) in a teleost fish, the medaka, Oryzias latipes2007
Author(s)
Y. Ohmuro-Matsuyama, K. Okubo, M. Matsuda, S. Ijiri, D. Wang, G. Guan, T. Suzuki, M. Matsuyama, K. Morohashi, Y. Nagahama
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Journal Title
Mol. Repro. Dev. 74
Pages: 1065-1071
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[Journal Article] Atrazine-induced aromatase expression is SF-1- dependent: Implications for endocrine disruption in wildlife and reproductive cancers in humans2007
Author(s)
W. Fan, T. Yanase, H. Morinaga, S. Gondo, T. Okabe, M. Nomura, T. Komatsu, K. Morohashi, T.B. Hayes, R. Takayanagi, H. Nawata
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Journal Title
Environmental Health Perspectives 115
Pages: 720-727
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[Journal Article] Foxl2 up-regulates aromatase gene transcription in a female-specific manner by binding to the promoter as well as interacting with Ad4BP/SF-12007
Author(s)
D. Wang, T. Kobayashi, L. Shou, Y. Ohmuro- Matsuyama, G. Guan, S. Ijiri, F. Sakai, M. Matsuda, Y. Shibata, K. Okubo, K. Morohashi, Y. Nagahama
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Journal Title
Mol. Endocrinol. 21
Pages: 712-725
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[Journal Article] CXorf6 is a causative gene for hypospadias2006
Author(s)
M. Fukami, Y. Wada, K. Miyabayashi, I. Nishino, T. Hasegawa, G. Camerino, C. Kretz, A. Buj- Bello, J. Laporte, G. Yamada, K. Morohashi, T. Ogata
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Journal Title
Nature Genetics 38
Pages: 1369-1371
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[Journal Article] A steroidogenic cell line with differentiation potential from mouse granulosa cells, transfected with Ad4BP and SV40 large T antigen genes2005
Author(s)
Kamei Y, Aoyama Y, Fujimoto T, Kenmotsu N, Kishi C, Koushi M, Sugano S, Morohashi K, Kamiyama R, Asakai R.
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Journal Title
J. Endocrinol. 185
Pages: 187-195
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[Journal Article] SUMO-1 modification of the synergy control motif of Ad4BP/SF-1 regulates synergistic transcription between Ad4BP/SF-1 and Sox92004
Author(s)
T. Komatsu, H. Mizusaki, T. Mukai, H. Ogawa, D. Baba, M. Shirakawa, S. Hatakeyama, K. Nakayama, H. Yamamoto, A. Kikuchi, K. Morohashi
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Journal Title
Mol. Endocrinol. 18
Pages: 2451-2462
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[Journal Article] Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation2004
Author(s)
M. Kato, S. Das, K. Petras, K. Kitamura, K.Morohashi, D. N. Abuelo, M. Barr, D. Bonneau,A. Brady, N. J. Carpenter, F. Frisone, T.Fukuda, R.Guerrini, E. Iida, M. Itoh, A. F. Lewanda, Y.Nanba, A. Oka, V. K. Proud, K. L. Russel, P.Saugier-Veber, S. L. Schelley, A. Selicorni, R.Shaner, M. Silengo, F. Stewart, N. Sugiyama, J. Toyama, A. Toutain, A. L. Vargas, M. Yanazawa, E. H. Zackai, W. B. Dobyns
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Journal Title
Human Mutation 23
Pages: 147-159
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[Presentation] Genetic program of gonad differentiation
Author(s)
K. Morohashi, Y. Ishimaru, M. Zubair, S. Oka, K. Miyabayashi, M. Kusaka, Y. Shima, T. Baba, H. Ogawa, H. Yoshioka, Y. Katoh-Fukui
Organizer
16th Lake Shirakaba Conference
Place of Presentation
Grenada
Year and Date
00001206-00001207
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[Presentation] Regulation of Ad4BP/SF-1 by SUMO
Author(s)
T. Komatsu, M. Tsuchiya, H. Ogawa, K. Morohashi
Organizer
The Fourth NIBB-EMBL Symposium Biology of Protein Conjugation-Structure and Function
Place of Presentation
Okazaki, Japan
Year and Date
00001203-00001205
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[Presentation] ワークショップReproduction & Gametology Abnormal epithelial cell polarity and migration of Emx2 KO embryonic gonads induced by ectopic EGFR expression
Author(s)
M. Kusaka, Y. Katoh-Fukui, H. Ogawa, K. Miyabayashi, T. Baba, N. Sugiyama, Y. Sugimoto, Y. Okuno, R. Kodama, A. Iizuka-Kogo, T. Senda, S. Aizawa, K. Morohashi
Organizer
第41回日本発生生物学会
Place of Presentation
徳島
Year and Date
00000528-00000530
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[Presentation] Genetic Program of Gonad Differentiation
Author(s)
K. Morohashi, Y. Ishimaru, M. Zubair, S. Oka, K. Miyabayashi, M. Kusaka, Y. Shima, T. Baba, H. Ogawa, H. Yoshioka, Y. Katho-Fukui
Organizer
The 52nd NIBB conference, Reproductive Strategies
Place of Presentation
Okazaki, Japan
Year and Date
00000120-00000123
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[Presentation] Mechanism for asymmetric gonad development in birds0
Author(s)
H. Yoshioka, Y. Ishimaru, T. Komatsu, M. Kasahara, Y. Katoh-Fukui, K. Morohashi
Organizer
International Symposium on "Molecular Mechanisms of Sex Determination and Differentiation" at the 77th Annual Meeting of the Zoological Society of Japan
Place of Presentation
Matsue, Japan
Year and Date
00000921
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