卵丘細胞のERKとPKB系に着目した哺乳動物卵子減数分裂再開制御因子の探索

• Project Area: The germline: its developmental cycle and epigenome network
• Project/Area Number: 21028014
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Hiroshima University
• Principal Investigator: 島田 昌之 広島大学, 大学院・生物圏科学研究科, 准教授 (20314742)
• Co-Investigator(Kenkyū-buntansha): 山下 泰尚 県立広島大学, 生命環境学部, 准教授 (50452545)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥6,400,000 (Direct Cost: ¥6,400,000); Fiscal Year 2010: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2009: ¥3,200,000 (Direct Cost: ¥3,200,000)
• Keywords: 卵巣 / 排卵 / 卵成熟 / 減数分裂 / IVM / 成長因子 / シグナル伝達 / 遺伝子発現 / 卵丘細胞 / neuregulin 1 / sphingogosine 1 kinase / 卵子 / cAMP

Research Abstract

卵成熟過程における卵丘細胞のERK1/2系を活性化させるEGF like factorに着目し,EGF like factorの一種であるamphiregulin (AREG)が,p38MAP kinaseやPKA依存的に発現することを見いだした.さらに,AREGはADAM17に修飾され活性型となるが,このADAM17の発現にプロジェステロンが関与していることを初めて明らかとした。卵丘細胞のERK1/2系は,卵の減数分裂を促進し,これをneuregulin1によるPKB系が抑制すること,この両者のバランスにより発生能を伴った卵の成熟が起こることも明らかとした.このneuregulin1は,sphingosineをsphigosine 1 phosphate (S1P)に変換するSPHK1の発現を正に制御し,S1Pが卵に作用して,cAMP濃度上昇を介して,卵の減数分裂を遅延させている可能性も示された.以上の結果から,AREGによるERK1/2が卵の減数分裂を正に制御し,neuregulin1によるPKB系が,S1P産生を介して負に制御する仕組みが示された.この成果は,ブタ卵における新たな体外成熟培養法の開発につながり,時期特異的に両者を添加する培養系により,体外受精後の胚盤胞期胚への発生率が有意に向上したことから,今後,様々な種への応用を目指していく計画である.

Research Products

• [Journal Article] LH induces Neuregulin 1 (NRG1) type III specific transcripts that interact with EGF-like factor pathways to control granulosa cell differentiation and oocyte maturation. (2011)
  • Author(s): Noma N.
  • Journal Title: Mol Endocrinol Volume: 25(1) Pages: 104-116
  • Peer Reviewed
• [Journal Article] The key signaling cascades in granulosa cells during follicular development and ovulation process (2011)
  • Author(s): Shimada M
  • Journal Title: J Mamm Ova Res Volume: (In press)
  • NAID: 10028124268
  • Peer Reviewed
• [Journal Article] Progesterone is essential for maintenance of Tace/Adam17 mRNA expression, but not EGF-like factor, in cumulus cells, which enhances EGF receptor signaling pathway during in vitro maturation of porcine COCs (2010)
  • Author(s): Yamashita Y.
  • Journal Title: J Reprod Dev Volume: 56(3) Pages: 315-323
  • NAID: 10026434172
  • Peer Reviewed
• [Journal Article] Murine sperm expresses Toll-like receptor (TLR) family that responds to the pathogens released from virus, and decreases fertilization ability by the stimuli. (2010)
  • Author(s): Mihara T.
  • Journal Title: J Mamm Ova Res Volume: 27 Pages: 136-143
  • Peer Reviewed
• [Journal Article] Possible involvement of phosphatidylinositol 3-kinase in the maintenance of metaphase II arrest in porcine oocytes matured in vitro. (2010)
  • Author(s): Ito J.
  • Journal Title: Anim Sci J Volume: 81 Pages: 42-47
  • Peer Reviewed
• [Journal Article] β-Catenin (CTNNB1) Promotes Preovulatory Follicular Development but Represses LH-Mediated Ovulation and Luteinization. (2010)
  • Author(s): Fan HY.
  • Journal Title: Mol Endocrinol Volume: 24(8) Pages: 1529-1542
  • Peer Reviewed
• [Journal Article] ERK1/2の活性化増強システムが,卵子成熟,卵丘細胞の膨潤,顆粒膜細胞の黄体化に必須である (2010)
  • Author(s): 川島一公
  • Journal Title: 日本生殖内分泌学会 Volume: 15 Pages: 35-40
  • Peer Reviewed
• [Journal Article] Progesterone is essential for mailtenance of Tace/Adam 17 mRNA expression, but not EGF-like factor, in cumulus cells, which enhances EGF receptor signaling pathway during in vitro maturation of prcine COCs (2010)
  • Author(s): Yamashita Y
  • Journal Title: J Reprod Dev (In press)
  • Peer Reviewed
• [Journal Article] Possible involvement of phosphatidylinositol 3-kinase in the maintenance of metaphase II attest in porcine oocytes matured in vitro. (2010)
  • Author(s): Ito J
  • Journal Title: Anim. Sci J (DOI:10.1111/j.1740-0929.2009.00717.x)
  • Peer Reviewed
• [Journal Article] Cumulus cells are an essential mediator of ovulation stimuli from granulosa cells to oocyte (Review article) (2010)
  • Author(s): Shimada M
  • Journal Title: J Mamm Ova Res (In press)
  • Peer Reviewed
• [Journal Article] Activation of PKA, p38MAPK and ERK1/2 by gonadotropils in cumulus cells is critical for induction of EGF-like factor and TACE/ADAM 17 gene expression during in vitro maturation of porcine COCs (2009)
  • Author(s): Yamashita Y
  • Journal Title: J Ovarian Res 2 Pages: 20-20
  • Peer Reviewed
• [Journal Article] ERK1/2 in ovarian granulosa cells are critical for female fertility (2009)
  • Author(s): Heng-Yu Fan
  • Journal Title: Science 324 Pages: 938-941
  • Peer Reviewed
• [Journal Article] IL6 : an autocrine regulator of the mouse cumulus cell-oocyte complex expansion process. (2009)
  • Author(s): Zhilin Liu
  • Journal Title: Endocrinology 150 Pages: 3360-3368
  • Peer Reviewed
• [Journal Article] 卵子卵丘細胞複合体と卵子形成 (2009)
  • Author(s): 鳥田昌之
  • Journal Title: J Mamm Ova Res 26 Pages: 189-194
  • Peer Reviewed
• [Presentation] 卵子成熟を制御する顆粒膜細胞分泌因子 (2010)
  • Author(s): 島田昌之
  • Organizer: 日本生殖内分泌学会
  • Place of Presentation: 大阪府吹田市(招請講演)
  • Year and Date: 2010-11-20
• [Presentation] 膨化した卵丘細胞卵子複合体に蓄積する抗菌ペプチドの機能解析 (2010)
  • Author(s): 三原敏敬
  • Organizer: 日本生殖内分泌学会
  • Place of Presentation: 大阪府吹田市
  • Year and Date: 2010-11-20
• [Presentation] 卵胞発育,排卵過程の顆粒膜細胞におけるToll-like receptor familyの発現とその機能解析 (2010)
  • Author(s): 田畑慧
  • Organizer: 日本生殖医学会
  • Place of Presentation: 徳島市
  • Year and Date: 2010-11-11
• [Presentation] Cumulus cells are an essential mediator of ovulation stimuli from granulosa cells to oocyte (2010)
  • Author(s): 島田昌之
  • Organizer: 日本繁殖生物学会
  • Place of Presentation: 十和田市(招請講演)
  • Year and Date: 2010-09-04
• [Presentation] PGE2によるERK1/2のポジティブフィードバック機構がブタ卵丘細胞卵子複合体の卵丘細胞の膨潤と卵子成熟に必須である (2010)
  • Author(s): 山下泰尚
  • Organizer: 日本繁殖生物学会
  • Place of Presentation: 十和田市
  • Year and Date: 2010-09-02
• [Presentation] 凍結精液の作製とその利用法を考える-「きちんと凍結する」,「上手に融かす」,「最適条件で受(授)精させる」- (2010)
  • Author(s): 島田昌之
  • Organizer: 日本受精着床学会
  • Place of Presentation: 横浜市(招請講演)
  • Year and Date: 2010-07-28
• [Presentation] 顆粒膜細胞に発現するALDH1 familyが,産生されるアセトアルデヒドを分解し,排卵前卵胞への発育を促進する (2010)
  • Author(s): 川合智子
  • Organizer: 日本哺乳動物卵子学会
  • Place of Presentation: 新潟市
  • Year and Date: 2010-05-29
• [Presentation] The innate immune functions of male and female germ cells-The expression of TLR family reduces the risk of infection problem from fetus (2010)
  • Author(s): 島田昌之
  • Organizer: 30^<th> annual meeting of American society of reproductive immunology
  • Place of Presentation: ピッツバーグ,アメリカ合衆国(招請講演)
  • Year and Date: 2010-05-17
• [Presentation] 卵丘細胞におけるERK1/2の持続的な活性化機構とその卵子成熟に果たす意義 (2010)
  • Author(s): 山下泰尚
  • Organizer: 第112回日本畜産学会大会
  • Place of Presentation: 東京
  • Year and Date: 2010-03-29
• [Presentation] 卵子の受精後の発生能を高める仕組みの解明とそのIVMへの応用 (2010)
  • Author(s): 島田昌之
  • Organizer: 第5回日本生殖再生医学会シナポジウム
  • Place of Presentation: 東京
  • Year and Date: 2010-02-25
• [Presentation] 卵胞発育過程に生産されるアセトアルデヒドのアポトーシス誘導作用とアセトアルデヒド脱水素酵素(ALDH)発現の意義 (2010)
  • Author(s): 川合智子
  • Organizer: 第5回日本生殖再生医学会
  • Place of Presentation: 東京
  • Year and Date: 2010-02-25
• [Presentation] 顆粒膜細胞で発現するNeuregulin-1(NRG1)は,Sphingosine-1-Phosphate(S1P)の産生を介して卵子の減数分裂進行速度を調整し,発生能を獲得させる (2009)
  • Author(s): 川島一公
  • Organizer: 第14回日本生殖内分泌学会大会 学術奨励賞受賞演題
  • Place of Presentation: 東京
  • Year and Date: 2009-11-28
• [Presentation] 排卵期特異的に顆粒膜細胞に発現するNeuregulin 1の発現機構とその機能解析 (2009)
  • Author(s): 野間紀孝
  • Organizer: 第102回日本繁殖生物学会大会
  • Place of Presentation: 奈良
  • Year and Date: 2009-09-13
• [Presentation] 排卵刺激による卵胞環境の段階的誘導(sequential induction)が卵子成熟を制御する (2009)
  • Author(s): 島田昌之
  • Organizer: 第27回日本受精着床学会 教育講演
  • Place of Presentation: 京都
  • Year and Date: 2009-08-05
• [Presentation] Neuregulin 1 is a novel oocyte maturation regulatory factor expressed in granulosa cells during ovulation process in mice (2009)
  • Author(s): Shimada M
  • Organizer: 42^<th> Annual Meeting of Society for the Study of Reproduction, oral presentation
  • Place of Presentation: Pittsburgh, USA
  • Year and Date: 2009-07-28
• [Presentation] Neuregulin 1 is a cumulus cell-secreted factor that maintains the cumulus cell functions after ovulation stage, to enhance fertilization and developmental competence of porcine oocytes (2009)
  • Author(s): Kawashima I
  • Organizer: 42^<th> Annual Meeting of Society for the Study of Reproduction
  • Place of Presentation: Pittsburgh, USA
  • Year and Date: 2009-07-28
• [Presentation] The involvement of Toll-like receptor family expressed on cumulus cells in fertilization (2009)
  • Author(s): Shimada M
  • Organizer: 12^<th> International symposium of Immunology of Reproduction, invited speaker
  • Place of Presentation: Varna, Bulgaria
  • Year and Date: 2009-06-18
• [Presentation] 顆粒膜細胞特異的ERK1/2遺伝子欠損マウスを用いたLHサージによる卵胞内エストロジェン濃度低下が誘起する排卵機構の解析 (2009)
  • Author(s): 田畑慧
  • Organizer: 第49回日本哺乳動物卵子学会大会
  • Place of Presentation: 東京
  • Year and Date: 2009-05-16
• [Remarks]
  • URL: http://home.hiroshima-u.ac.jp/seisyoku/index.html