Analysis of the mechanism regulating ovulation by GnRH surge generator

• Project/Area Number: 16H06206
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Animal production science
• Research Institution: The University of Tokyo
• Principal Investigator: Matsuda Fuko 東京大学, 大学院農学生命科学研究科(農学部), 准教授 (10608855)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥23,790,000 (Direct Cost: ¥18,300,000、Indirect Cost: ¥5,490,000); Fiscal Year 2019: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2018: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2016: ¥13,780,000 (Direct Cost: ¥10,600,000、Indirect Cost: ¥3,180,000)
• Keywords: 繁殖 / 反芻家畜 / 細胞株 / GnRHニューロン / キスペプチンニューロン / 獣医学 / 畜産学 / 生理学 / 脳・神経 / 細胞・組織 / 応用動物 / 神経科学

Outline of Final Research Achievements

The follicular cyst, one of the most important reproductive disorders in cattle, is suggested to be partly caused by the defect of gonadotropin-releasing hormone (GnRH) surge generator that induces ovulation in the brain. However, the mechanism regulating the GnRH surge generator has not been elucidated especially in domestic animals. This study aimed to clarify the mechanism regulating the GnRH surge generator in domestic ruminants. I succeeded to establish cell lines (kisspeptin neuron cell lines and GnRH neuron cell lines) that can be used to analyze the regulation mechanism of reproductive center in domestic ruminants at a cellular level.

Academic Significance and Societal Importance of the Research Achievements

本研究で樹立したヤギのキスペプチンニューロン細胞株およびGnRHニューロン細胞株は、家畜で唯一の視床下部由来神経細胞株であり、ウシを含む反芻家畜における繁殖中枢制御メカニズムの解析や、繁殖制御剤の開発に利用できる。その結果、反芻家畜の中枢性繁殖障害の発症機序が解明され、ウシの受胎率向上に資する新たな治療法が開発されると期待できる。

Research Products

• [Journal Article] Estrogen increases <i>KISS1</i> expression in newly generated immortalized <i>KISS1</i>-expressing cell line derived from goat preoptic area (2021)
  • Author(s): OSHIMO Yukina、MUNETOMO Arisa、MAGATA Fumie、SUETOMI Yuta、SONODA Shuhei、TAKEUCHI Yukari、TSUKAMURA Hiroko、OHKURA Satoshi、MATSUDA Fuko
  • Journal Title: Journal of Reproduction and Development Volume: 67 Issue: 1 Pages: 15-23
  • DOI: 10.1262/jrd.2020-053
  • NAID: 130007986318
  • ISSN: 0916-8818, 1348-4400
  • Peer Reviewed / Open Access
• [Journal Article] Reduction of arcuate kappa-opioid receptor-expressing cells increased luteinizing hormone pulse frequency in female rats (2021)
  • Author(s): Dai Mingdao、Nakamura Sho、Takahashi Chudai、Sato Marimo、Munetomo Arisa、Magata Fumie、Uenoyama Yoshihisa、Tsukamura Hiroko、Matsuda Fuko
  • Journal Title: Endocrine Journal Volume: 68 Issue: 8 Pages: 933-941
  • DOI: 10.1507/endocrj.EJ20-0832
  • NAID: 130008079310
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Testosterone regulation on quiescin sulfhydryl oxidase 2 synthesis in the epididymis (2021)
  • Author(s): Wang Tse-En、Minabe Shiori、Matsuda Fuko、Li Sheng-Hsiang、Tsukamura Hiroko、Maeda Kei-Ichiro、Smith Lee、O’Hara Laura、Gadella Bart M、Tsai Pei-Shiue
  • Journal Title: Reproduction Volume: 161 Issue: 5 Pages: 593-602
  • DOI: 10.1530/rep-20-0629
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Peripheral administration of SB223412, a selective neurokinin-3 receptor antagonist, suppresses pulsatile luteinizing hormone secretion by acting on the gonadotropin-releasing hormone pulse generator in estrogen-treated ovariectomized female goats. (2020)
  • Author(s): Sasaki T, Sonoda T, Tatebayashi R, Kitagawa Y, Oishi S, Yamamoto K, Fujii N, Inoue N, Uenoyama Y, Tsukamura H, Maeda KI, Matsuda F, Morita Y, Matsuyama S, Ohkura S.
  • Journal Title: J Reprod Dev Volume: - Issue: 4 Pages: 351-357
  • DOI: 10.1262/jrd.2019-145
  • NAID: 130007888728
  • Peer Reviewed / Open Access
• [Journal Article] Inducible Kiss1 knockdown in the hypothalamic arcuate nucleus suppressed pulsatile secretion of luteinizing hormone in male mice (2020)
  • Author(s): Shiori Minabe, Sho Nakamura, Eri Fukushima, Marimo Sato, Kana Ikegami, Teppei Goto, Makoto Sanbo, Masumi Hirabayashi, Junko Tomikawa, Takuya Imamura, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei-Ichiro Maeda, Fuko Matsuda
  • Journal Title: Journal of Reproduction and Development Volume: Epub Issue: 4 Pages: 369-375
  • DOI: 10.1262/jrd.2019-164
  • NAID: 130007888724
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of immortalised cell lines derived from female Shiba goat KNDy and GnRH neurones. (2020)
  • Author(s): Suetomi Y, Tatebayashi R, Sonoda S, Munetomo A, Matsuyama S, Inoue N, Uenoyama Y, Takeuchi Y,Tsukamura H, Ohkura S, Matsuda F.
  • Journal Title: Neuroendocrinology Volume: 32(6) Issue: 6 Pages: 12857-12857
  • DOI: 10.1111/jne.12857
  • Peer Reviewed
• [Journal Article] Role of kisspeptin neurons as a GnRH surge generator: Comparative aspects in rodents and non‐rodent mammals (2019)
  • Author(s): Matsuda Fuko、Ohkura Satoshi、Magata Fumie、Munetomo Arisa、Chen Jing、Sato Marimo、Inoue Naoko、Uenoyama Yoshihisa、Tsukamura Hiroko
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 45 Issue: 12 Pages: 2318-2329
  • DOI: 10.1111/jog.14124
  • Peer Reviewed
• [Journal Article] Peripheral administration of κ-opioid receptor antagonist stimulates gonadotropin-releasing hormone pulse generator activity in ovariectomized, estrogen-treated female goats (2019)
  • Author(s): Sasaki T.、Ito D.、Sonoda T.、Morita Y.、Wakabayashi Y.、Yamamura T.、Okamura H.、Oishi S.、Noguchi T.、Fujii N.、Uenoyama Y.、Tsukamura H.、Maeda K.I.、Matsuda F.、Ohkura S.
  • Journal Title: Domestic Animal Endocrinology Volume: 68 Pages: 83-91
  • DOI: 10.1016/j.domaniend.2018.12.011
  • Peer Reviewed / Open Access
• [Journal Article] Neonatal Estrogen Causes Irreversible Male Infertility via Specific Suppressive Action on Hypothalamic Kiss1 Neurons (2019)
  • Author(s): Minabe Shiori、Sato Marimo、Inoue Naoko、Watanabe Youki、Magata Fumie、Matsuda Fuko、Uenoyama Yoshihisa、Ozawa Hitoshi、Tsukamura Hiroko
  • Journal Title: Endocrinology Volume: 160 Issue: 5 Pages: 1223-1233
  • DOI: 10.1210/en.2018-00732
  • Peer Reviewed / Open Access
• [Journal Article] Mouse quiescin sulfhydryl oxidases exhibit distinct epididymal luminal distribution with segment-specific sperm surface associations† (2018)
  • Author(s): Wang Tse-En、Li Sheng-Hsiang、Minabe Shiori、Anderson Amanda L、Dun Matthew D、Maeda Kei-Ichiro、Matsuda Fuko、Chang Hui-Wen、Nixon Brett、Tsai Pei-Shiue Jason
  • Journal Title: Biology of Reproduction Volume: 99 Pages: 1022-1033
  • DOI: 10.1093/biolre/ioy125
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Evaluation of heat stress response in crossbred dairy cows under tropical climate by analysis of heart rate variability (2018)
  • Author(s): Bun, C., Watanabe, Y., Uenoyama, Y., Inoue, N., Ieda, N., Matsuda, F., Tsukamura, H., Kuwahara, M., Maeda, K.-I., Ohkura, S. and Pheng, V.
  • Journal Title: Journal of Veterinary Medical Science Volume: 80 Issue: 1 Pages: 181-185
  • DOI: 10.1292/jvms.17-0368
  • NAID: 130006331058
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SB223412, a neurokinin-3 receptor-selective antagonist, suppresses testosterone secretion in male guinea pigs (2017)
  • Author(s): Nakamura Sho、Ito Yoshiko、Yamamoto Koki、Takahashi Chudai、Dai Mingdao、Tanahashi Miyu、Uenoyama Yoshihisa、Tsukamura Hiroko、Oishi Shinya、Maeda Kei-ichiro、Matsuda Fuko
  • Journal Title: Theriogenology Volume: 102 Pages: 183-189
  • DOI: 10.1016/j.theriogenology.2017.07.053
  • Peer Reviewed
• [Journal Article] 中枢からのアプローチ：新たな神経内分泌メカニズムを利用した繁殖制御 (2017)
  • Author(s): 松田二子、前多敬一郎、大蔵 聡、上野山賀久、束村博子
  • Journal Title: 臨床獣医 Volume: 35 Pages: 98-101
• [Journal Article] Immunohistochemical characterization of the arcuate kisspeptin/neurokinin B/dynorphin (KNDy) and preoptic kisspeptin neuronal populations in the hypothalamus during the estrous cycle in heifers. (2016)
  • Author(s): Hassaneen, A.S.A., Naniwa, Y., Suetomi, Y., Matsuyama, S., Kimura, K., Ieda, N., Inoue, N., Uenoyama, Y., Tsukamura, H., Maeda, K.-I., Matsuda, F. and Ohkura, S.
  • Journal Title: Journal of Reproduction and Development Volume: 62 Issue: 5 Pages: 471-477
  • DOI: 10.1262/jrd.2016-075
  • NAID: 130005431286
  • Peer Reviewed / Open Access
• [Presentation] 雌ヤギ由来KNDyニューロンおよびGnRHニューロン不死化細胞株の樹立 (2020)
  • Author(s): 松田 二子、末富 祐太、舘林 亮輝、園田 修平、棟朝 亜理紗、松山 秀一、井上 直子、上野山 賀久、武内 ゆかり、束村 博子、大蔵 聡
  • Organizer: 第25回日本生殖内分泌学会学術集会
• [Presentation] グルコース濃度低下時に生理機能を制御する神経伝達経路の探索 (2019)
  • Author(s): 佐藤真梨萌、美辺詩織、真方文絵、束村博子、松田二子
  • Organizer: 第37回内分泌代謝学サマーセミナー
• [Presentation] ヤギ視索前野由来キスペプチンニューロン不死化細胞株の樹立 (2019)
  • Author(s): 大下雪奈、棟朝亜理紗、末富祐太、真方文絵、束村博子、大蔵聡、松田二子
  • Organizer: 第112回日本繁殖生物学会学術集会
• [Presentation] レンチウイルスベクターを用いたラット視床下部におけるκオピオイド受容体（KOR）陽性ニューロンの可視化とその局在および投射先の解析 (2019)
  • Author(s): 棟朝亜理紗、中島大貴、前多敬一郎、松田二子
  • Organizer: 第112回日本繁殖生物学会学術集会
• [Presentation] 家畜における繁殖の神経内分泌学－基礎的知見と臨床応用の可能性－ (2019)
  • Author(s): 松田二子、大蔵聡
  • Organizer: 第126回日本畜産学会大会
  • Invited
• [Presentation] 低栄養による性腺刺激ホルモン分泌の抑制を担う神経伝達経路とグルコースセンサーの同定 (2019)
  • Author(s): 佐藤真梨萌、美辺詩織、渡辺雄貴、後藤哲平、三宝誠、平林真澄、真方文絵、束村博子、松田二子
  • Organizer: 第112回日本繁殖生物学会学術集会
• [Presentation] 栄養による生殖機能・血糖・摂食調節を担うエネルギーセンサーと神経経路の同定 (2019)
  • Author(s): 佐藤真梨萌、美辺詩織、渡辺雄貴、後藤哲平、三宝誠、平林真澄、井上直子、上野山賀久、真方文絵、束村博子、松田二子
  • Organizer: 第46回日本神経内分泌学会学術集会
• [Presentation] オスニホンザルへのニューロキニンB受容体拮抗剤皮下インプラントによる繁殖抑制効果の検証 (2019)
  • Author(s): 迫野貴大、陳晶、真方文絵、佐々木拓弥、山本昂輝、大石真也、井上直子、上野山賀久、束村博子、鈴木樹理、松田二子
  • Organizer: 第112回日本繁殖生物学会学術集会
• [Presentation] The kappa opioid receptor (KOR)-expressing neurons localize in the ventromedial hypothalamic nucleus and project to KNDy neurons, the GnRH pulse generator, in rats. (2019)
  • Author(s): Arisa MUNETOMO, Daiki NAKAJIMA, Kei-Ichiro MAEDA, Fuko MATSUDA
  • Organizer: ENDO2019
  • Int'l Joint Research
• [Presentation] Kisspeptin is required for perinatal testosterone surge in male rats (2019)
  • Author(s): Jing CHEN, Shiori MINABE, Chudai TAKAHASHI, Arisa MUNETOMO, Fumie MAGATA, Sho NAKAMURA, Yoshihisa UENOYAMA, Hiroko TSUKAMURA, Kei-ichiro MAEDA, Fuko MATSUDA
  • Organizer: ENDO2019
  • Int'l Joint Research
• [Presentation] Inducible Kiss1 knockout in the hypothalamic arcuate nucleus suppressed pulsatile LH secretion in male mice. (2019)
  • Author(s): Shiori Minabe, Sho Nakamura, Eri Fukushima, Naoko Inoue, Yoshihisa Uenoyama, Kei-ichiro Maeda, Hiroko Tsukamura, and Fuko Matsuda
  • Organizer: ENDO2019
  • Int'l Joint Research
• [Presentation] 家畜における生殖技術の進歩 (2018)
  • Author(s): 松田二子、真方文絵、束村博子、前多敬一郎
  • Organizer: 第91回 日本内分泌学会学術集会
  • Invited
• [Presentation] キスペプチンニューロンによる繁殖制御メカニズムの新知見 (2018)
  • Author(s): 松田二子
  • Organizer: 第161回 日本獣医学会学術集会
  • Invited
• [Presentation] ニューロキニンB受容体拮抗剤の経口投与はパルス状LH分泌を抑制する (2018)
  • Author(s): 佐々木 拓弥、園田 朋也、大石 真也、藤井 信孝、森田 康広、松山 秀一、井上 直子、上野山 賀久、束村 博子、前多 敬一郎、松田 二子、大蔵 聡
  • Organizer: 第111回 日本繁殖生物学会大会
• [Presentation] Kisspeptin is required to induce testosterone surge in perinatal male rats. (2018)
  • Author(s): Jing Chen, Shiori Minabe, Chudai Takahashi, Kei-ichiro Maeda, Fuko Matsuda
  • Organizer: 第111回 日本繁殖生物学会大会
• [Presentation] ラットKORおよびGPR54プロモーター領域の同定とKORニューロンおよびGPR54ニューロンの投射先の可視化 (2018)
  • Author(s): 棟朝亜理紗、中島大貴、前多敬一郎、松田二子
  • Organizer: 第45回 日本神経内分泌学会学術集会
• [Presentation] Establishment of Immortalized Cell Lines Derived from Rat AVPV and ARC Kisspeptin Neurons (2018)
  • Author(s): Kei Horihata, Naoko Inoue, Nahoko Ieda, Yoshihisa Uenoyama, Yuta Suetomi, Fuko Matsuda, Kei-ichiro Maeda, Hiroko Tsukamura
  • Organizer: ENDO 2018 (Annual meeting of Endocrine Society)
  • Int'l Joint Research
• [Presentation] TALEN-mediated Cre recombinase knockin in KISS1 locus of goat embryonic fibroblasts (2017)
  • Author(s): Ryoki Tatebayashi, Tetsushi Sakuma, Takashi Yamamoto, Satoshi Ohkura, Fuko Matsuda
  • Organizer: Fourth World Congress of Reproductive Biology
  • Int'l Joint Research
• [Presentation] Establishment and evaluation of rat kisspeptin neuronal cell lines (2017)
  • Author(s): Kei Horihata, Ai Takahashi, Naoko Inoue, Nahoko Ieda, Yoshihisa Uenoyama, Yuta Suetomi, Fuko Matsuda, Kei-ichiro Maeda, Hiroko Tsukamura
  • Organizer: Fourth World Congress of Reproductive Biology
  • Int'l Joint Research
• [Presentation] 哺乳類の生殖中枢の制御機構解明に資する ラットキスペプチンニューロン不死化細胞株の作出 (2017)
  • Author(s): 堀畑慶、井上直子、家田菜穂子、上野山賀久、末富祐太、松田二子、前多敬一郎、束村博子
  • Organizer: 東海畜産学会
• [Presentation] 遺伝子改変ラットを用いたkappa opioid receptor(KOR)発現細胞の解析 (2016)
  • Author(s): 高橋 宙大，後藤 哲平，平林 真澄，中村 翔，戴 明道，池上 花奈, 松田二子、上野山賀久，束村博子，前多 敬一郎
  • Organizer: 第43回日本神経内分泌学会学術集会
  • Place of Presentation: アクトシティ浜松（静岡県浜松市）
  • Year and Date: 2016-10-14
• [Presentation] シバヤギKNDyニューロン不死化細胞株の樹立 (2016)
  • Author(s): 末富祐太，舘林亮輝，束村博子，大蔵聡，松田二子
  • Organizer: 第109回日本繁殖生物学会大会
  • Place of Presentation: 麻布大学（東京都相模原市）
  • Year and Date: 2016-09-12
• [Presentation] ラットキスペプチンニューロン不死化細胞株の樹立 (2016)
  • Author(s): 堀畑慶，家田菜穂子，井上直子，上野山賀久，末富祐太，松田二子，前多敬一郎，束村博子
  • Organizer: 第109回日本繁殖生物学会大会
  • Place of Presentation: 麻布大学（東京都相模原市）
  • Year and Date: 2016-09-12
• [Presentation] Modification of KISS1 gene in goat embryonic fibroblasts using TALEN (2016)
  • Author(s): Ryoki Tatebayashi, Tetsushi Sakuma, Takashi Yamamoto, Satoshi Ohkura, Fuko Matsuda
  • Organizer: International Symposium on Pituitary Gland and Related Systems 2016
  • Place of Presentation: ホノルル（米国）
  • Year and Date: 2016-09-01
  • Int'l Joint Research
• [Presentation] Establishment of immortalized cell lines derived from cattle GnRH neurons (2016)
  • Author(s): Riho OZAKI, Yuta SUETOMI, Shuichi MATSUYAMA, Koji KIMURA, Satoshi OHKURA, Fuko Matsuda
  • Organizer: International Symposium on Pituitary Gland and Related Systems 2016
  • Place of Presentation: ホノルル（米国）
  • Year and Date: 2016-09-01
  • Int'l Joint Research
• [Presentation] Establishment of a Neuronal Cell Line Derived from KNDy Neuron in a Goat (2016)
  • Author(s): Yuta Suetomi, Ryoki Tatebayashi, Hiroko Tsukamura, Satoshi Ohkura, Fuko Matsuda
  • Organizer: The 49th Annual Meeting of Society for the Study of Reproduction
  • Place of Presentation: サンディエゴ（米国）
  • Year and Date: 2016-07-16
  • Int'l Joint Research
• [Presentation] 排卵中枢キスペプチンニューロンの性分化には種差がある (2016)
  • Author(s): 松田二子、渡辺雄貴、大蔵聡、井上直子、上野山賀久、前多敬一郎、束村博子
  • Organizer: 第13回GPCR研究会
  • Place of Presentation: 日本科学未来館（東京都江東区）
  • Year and Date: 2016-05-13
• [Book] 動物学の百科事典（ストレスとホルモン） (2018)
  • Author(s): 公益社団法人日本動物学会（松田二子、前多敬一郎）
  • Total Pages: 800
  • Publisher: 丸善出版
  • ISBN: 9784621303092
• [Remarks] 東京大学獣医繁殖育種学教室
  • URL: http://www.vm.a.u-tokyo.ac.jp/ikushu/index.html
• [Remarks] 東京大学大学院農学生命科学研究科獣医繁殖育種学教室ホームページ
  • URL: http://www.vm.a.u-tokyo.ac.jp/ikushu/index.html