The physiological role of CD9 and exosomes in oviducts and uteri

• Project/Area Number: 23659788
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: National Research Institute for Child Health and Development
• Principal Investigator: MIYADO KENJI 独立行政法人国立成育医療研究センター, 生殖・細胞医療研究部, 室長 (60324844)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
• Keywords: 不妊 / 出産 / 子宮内膜上皮 / 再生 / CD9 / VEGF-A / エキソソーム / 子宮内膜 / 子宮 / VEGF

Research Abstract

In mammals, the female reproductive tract is remodeled cyclically throughout adult life. Despite the expression of CD9 in the epithelium of the uterus, its role is unclear. Here, we addressed this issue by examining fertilization-competent Cd9-/- mice expressing CD9-GFP in their eggs (Cd9-/-TG). Immunobiochemical analysis demonstrated that CD9 was present in the uterine secretions. Electron microscopic analysis revealed the extracellular matrix-like feature of CD9-containing structures. We also found that the litter size of Cd9-/-TG female mice was significantly reduced after their first birth. Histological analysis revealed severely delayed re-epithelialization of the endometrium both in vitro and in vivo in mice. The quantity of vascular endothelial growth factor-A (VEGF-A) was remarkably reduced in Cd9-/-TG female mice. These results provide the first evidence that CD9-mediated VEGF secretion plays a role in re-epithelialization of the uterus.

Research Products

• [Journal Article] Absence of CD9 reduces endometrial VEGF secretion and impairs uterine repair after parturition (2014)
  • Author(s): N Kawano, K Miyado, N Yoshii, S Kanai, H Saito, M Miyado, N Inagaki, Y Odawara, T Hamatani, A Umezawa
  • Journal Title: Scientific reports Volume: 4 Issue: 1 Pages: 4701-4701
  • DOI: 10.1038/srep04701
  • Peer Reviewed / Open Access
• [Journal Article] Derivation of human decidua-like cells from amnion and menstrual blood (2014)
  • Author(s): Sugawara K, Hamatani T, Yamada M, Ogawa S, Kamijo S, Kuji N, Akutsu H, Miyado K, Yoshimura Y, Umezawa A
  • Journal Title: Sci Rep Volume: 4 Issue: 1 Pages: 4599-4599
  • DOI: 10.1038/srep04599
  • Peer Reviewed / Open Access
• [Journal Article] Seminal vesicle protein SVS2 is required for sperm survival in the uterus (2014)
  • Author(s): N Kawano, N Araki, K Ybshida, THibino, N Ohnami, M Makino, S Kanai, H Hasuwa, M Yoshida, K Miyado, A Umezawa
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 111(11) Issue: 11 Pages: 4145-4150
  • DOI: 10.1073/pnas.1320715111
  • Peer Reviewed / Open Access
• [Journal Article] Age-associated telomere shortening in mouse oocytes (2013)
  • Author(s): Yamada-Fukunaga T, Yamada M, Hamatani T, Chikazawa N, Ogawa S, Akutsu H, Miura T, Miyado K, Tarin JJ, Kuji N, Umezawa A, Yoshimura Y
  • Journal Title: Reprod Biol Endocrinol Volume: 11 Issue: 1 Pages: 108-108
  • DOI: 10.1186/1477-7827-11-108
  • Peer Reviewed
• [Journal Article] β-catenin functions pleiotropically in differentiation and tumorigenesis in mouse embryo-derived stem cells (2013)
  • Author(s): Okumura N, Akutsu H, Sugawara T, Miura T, Takezawa Y, Hosoda A, Yoshida K, Ichida JK, Yamada M, Hamatani T, Kuji N, Miyado K, Yoshimura Y, Umezawa A
  • Journal Title: PLoS One Volume: 8(5) Issue: 5 Pages: 63265-63265
  • DOI: 10.1371/journal.pone.0063265
  • Peer Reviewed
• [Journal Article] Integration of the mouse sperm fertilization-related protein equatorin into the acrosome during spermatogenesis as revealed by super-resolution and immunoelectron microscopy (2013)
  • Author(s): Ito C, Yamatoya K, Yoshida K, Fujimura L, Hatano M, Miyado K, Toshimori K
  • Journal Title: Cell Tissue Res Volume: 352(3) Issue: 3 Pages: 739-750
  • DOI: 10.1007/s00441-013-1605-y
  • Peer Reviewed
• [Journal Article] テトラスパニンによる受精の膜融合制御 (2013)
  • Author(s): 宮戸健二
  • Journal Title: 医学のあゆみ Volume: Vol.244, No.2 Pages: 181-181
• [Journal Article] Critical role of exosomes in sperm-egg fusion and virus-induced cell-cell fusion (2013)
  • Author(s): Harada Y, Yoshida K, Kawano N, Miyado K
  • Journal Title: Reproductive Medicine and Biology Volume: 1 Pages: 1-1
  • Peer Reviewed
• [Journal Article] Beta-catenin functions pleiotropically in differentiation and tumorigenesis in mouse embryo-derived stem cells (2013)
  • Author(s): Okumura N, Akutsu H, Sugawara T, Miura T, Takezawa Y, Hosoda A, Yoshida K, Yamada M, Hamatani T, Miyado K, Yoshimura Y, Umezawa A
  • Journal Title: PLOS ONE Volume: 1 Pages: 1-1
  • Peer Reviewed
• [Journal Article] CD81 and CD9 work independently as extracellular components upon fusion of sperm and oocyt (2012)
  • Author(s): Ohnami N, Nakamura A, Miyado M, Sato M, Kawano N, Yoshida K, Harada Y, Takezawa Y, Kanai S, Ono C, Takahashi Y, Kimura K, Shida T, Miyado K, Umezawa A
  • Journal Title: Biol Open Volume: 1(7) Issue: 7 Pages: 640-647
  • DOI: 10.1242/bio.20121420
  • Peer Reviewed
• [Journal Article] Mamld1 deficiency significantly reduces mRNA expression levels of multiple genes expressed in mouse fetal Leydig cells but permits normal genital and reproductive development (2012)
  • Author(s): Miyado M, Nakamura M, Miyado K, Morohashi K, Sano S, Nagata E, Fukami M, Ogata T
  • Journal Title: Endocrinology Volume: 153(12) Issue: 12 Pages: 6033-6040
  • DOI: 10.1210/en.2012-1324
  • Peer Reviewed
• [Journal Article] Impaired fertilizing ability of Sodl-deficient mouse sperm during in-vitro fertilization. (2012)
  • Author(s): Tsunoda Satoshi, Kawano Natsuko, Miyado Kenji, Kim ura Naoko, Fujii Junichi.
  • Journal Title: Biology of reproduction Volume: 87 Issue: 5 Pages: 1-6
  • DOI: 10.1095/biolreprod.112.102129
  • Peer Reviewed
• [Journal Article] 卵由来エキソソームによる細胞融合の促進機構 (2012)
  • Author(s): 宮戸健二
  • Journal Title: 医学のあゆみ Volume: Vol.241,No.11 Pages: 861-862
• [Journal Article] CD9 is critical for cutaneous wound healing through JNK signaling. (2012)
  • Author(s): Zhang J, Dong J, Gu H, Yu S, Zhang X, Gou Y, Xu W, Burd A, Huang L, Miyado K, Huang Y, Chan HC.
  • Journal Title: Journal of Investigative Dermatology Volume: 132 Issue: 1 Pages: 226-236
  • DOI: 10.1038/jid.2011.268
  • Peer Reviewed
• [Journal Article] β-catenin is a molecular switch that regulates transition of cell-cell adhesion to fusion (2011)
  • Author(s): Takezawa Y, Yoshida K, Miyado K, Sato M, Nakamura A, Kawano N, Sakakibara K, Kondo T, Harada Y, Ohnami N, Kanai S, Miyado M, Saito H, Takahashi Y, Akutsu H, Umezawa A
  • Journal Title: Sci Rep Volume: 1 Issue: 1 Pages: 68-68
  • DOI: 10.1038/srep00068
  • Peer Reviewed
• [Journal Article] GSTT1 is upregulated by oxidative stress through p38-MK2 signaling pathway in human granulosa cells : possible association with mitochondrial activity (2011)
  • Author(s): Ito M, Imai M, Muraki M, Miyado K, Qin J, Kyuwa S, Yoshikawa Y, Hosoi Y, Saito H, Takahashi Y
  • Journal Title: Aging (Albany NY) Volume: 3(12) Pages: 1213-23
• [Journal Article] Lipid rafts : keys to sperm maturation, fertilization, and early embryogenesis (2011)
  • Author(s): Kawano N, Yoshida K, Miyado K, Yoshida M
  • Journal Title: J Lipids Volume: 2011 Pages: 264706-264706
  • DOI: 10.1155/2011/264706
  • Peer Reviewed
• [Journal Article] Lipid rafts enriched in monosialylGb5Cer carrying the stage-specific embryonic antigen-4 epitope are involved in development of mouse preimplantation embryos at cleavage stage (2011)
  • Author(s): Sato B, Katagiri YU, Miyado K, Okino N, Ito M, Akutsu H, Okita H, Umezawa A, Fujimoto J, Toshimori K, Kiyokawa N
  • Journal Title: BMC Dev Biol Volume: 11 Issue: 1 Pages: 22-22
  • DOI: 10.1186/1471-213x-11-22
  • Peer Reviewed
• [Journal Article] GSTT1 is upregulated by oxidative stress through p38-MK2 signaling pathway in human granulosa cells: possible association with mitochondrial activity. (2011)
  • Author(s): Ito M, Imai M, Muraki M, Miyado K, Qin J, Kyuwa S, Yoshikawa Y, Hosoi Y, Saito H, Takahashi Y.
  • Journal Title: Aging Volume: 3 Pages: 1213-1223
  • Peer Reviewed
• [Presentation] テトラスパニンを介した細胞融合の分子メカニズム、ワークショップ「4回膜貫通蛋白質の構造と機能解析の進展」 (2013)
  • Author(s): 宮戸健二
  • Organizer: 第36回日本分子生物学会年会
• [Presentation] テトラスパニンを介した細胞融合の分子メカニズム (2013)
  • Author(s): 宮戸健二
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド
  • Invited
• [Presentation] 受精の膜融合におけるCD9およびエキソソームの役割、シンポジウム「バイオイメージングにより明らかにされた動・植物の有性生殖メカニズム」 (2012)
  • Author(s): 宮戸健二
  • Organizer: 日本顕微鏡学会第68回学術講演会
• [Presentation] CD9 maintains uterine function through VEGF secretion from endometrial epithelium (2012)
  • Author(s): 宮戸健二、河野菜摘子、吉井紀子、金井誠也、梅澤明弘、浜谷敏生
  • Organizer: 日本分子生物学会
  • Place of Presentation: 福岡国際会議場
• [Presentation] PLCzeta is involved in spermatogenesis in mice (2012)
  • Author(s): 牧野麻亜子、伊藤昌彦、河野菜摘子、原田裕一郎、金井誠也、宮戸健二
  • Organizer: 日本分子生物学会
  • Place of Presentation: 福岡国際会議場
• [Presentation] 哺乳類における受精の膜融合を制御する分子メカニズム (2012)
  • Author(s): 宮戸健二
  • Organizer: 日本動物学会
  • Place of Presentation: 大阪大学
  • Invited
• [Presentation] マウス卵の受精におけるクエン酸合成酵素による卵活性化の可能性 (2012)
  • Author(s): 原田裕一郎、吉田恵一、金井誠也、河野菜摘子、岩尾康宏、宮戸健二
  • Organizer: 日本動物学会
  • Place of Presentation: 大阪大学
• [Presentation] 受精のメカニズム：精子と卵の膜融合を制御する分子機構 (2012)
  • Author(s): 宮戸健二
  • Organizer: 日本受精着床学会
  • Place of Presentation: 大阪国際会議場
  • Invited
• [Presentation] 精子と卵子の融合メカニズム：感染症と生殖をつなぐ構造体 (2011)
  • Author(s): 宮戸健二
  • Organizer: 第52回日本哺乳動物卵子学会
  • Place of Presentation: 国際医療福祉大学本校、大田原
• [Book] Role of CD9 in sperm-egg fusion and virus-induced cell fusion in mammals. Sexual Reproduction in Animals and Plants, edited by Sawada H, Inoue N, Iwano M (2014)
  • Author(s): Yoshida K, Kawano N, Harada Y, Miyado K
  • Publisher: Springer
• [Book] 動植物の受精学 - 共通性と多様性 - (2014)
  • Author(s): 澤田均, 編
  • Publisher: 化学同人
• [Book] In Embryology- Updates and Highlights on Classic Topics (2012)
  • Author(s): Imai M, Qin J, Yamakawa N, Miyado K, Umezawa A, Takahashi Y
  • Total Pages: 200
  • Publisher: InTech Open Publisher
• [Book] In Embryology- Updates and Highlights on Classic Topics (2012)
  • Author(s): Imai M, Qin J, Yamakawa N, Miyado K, Umezawa A, Takahashi Y.
  • Total Pages: 20
  • Publisher: InTech Open Publisher
• [Book] Role of CD9 in sperm-egg fusion and its general role in fusion phenomena. Cell Fusions, edited by Lars-Inge Larsson (2011)
  • Author(s): Kawano N, Harada Y, Yoshida K, Miyado K
  • Publisher: Springer
• [Remarks]
  • URL: http://www.ncchd.go.jp/research/nch/reproduction/staff_miyado.html