Regulation of oogenesis by the unique metabolic status in fetal germ cells

• Project/Area Number: 19H03231
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 44020:Developmental biology-related
• Research Institution: Tohoku University
• Principal Investigator: Matsui Yasuhisa 東北大学, 加齢医学研究所, 教授 (40241575)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 卵母細胞 / 代謝 / エピゲノム / MPC / TCA回路 / 生殖細胞 / エネルギー代謝 / ピルビン酸 / 転写 / 解糖系

Outline of Research at the Start

胎仔生殖細胞の卵母細胞への分化・成熟に伴う亢進したミトコンドリア代謝、および解糖系活性の変化の役割と制御機構を明らかにすることを目的とする。胎仔生殖細胞から卵母細胞への分化を再現できる胎仔卵巣の器官培養系で、着目する特定の代謝経路の阻害剤の効果を調べ、重要な代謝段階を絞り込み、遺伝子発現解析により代謝経路の下流で卵母細胞分化に関わる遺伝子候補を選択する。それらの遺伝子、および関与する代謝酵素遺伝子とその転写制御因子遺伝子の条件的ノックアウトをマウス個体で行い、卵母細胞形成における役割を明らかにする。

Outline of Final Research Achievements

This study aimed to show roles of energy metabolism in fetal mouse germ cells for oogenesis. We demonstrated that MPC2, a pyruvate carrier protein on mitochondrial membrane, and α-ketoglutarate in TCA cycle are crucial for early steps of oogenesis by using organ culture of fetal ovary and germ cell-specific knock-out mouse of Mpc2. In addition, we also found that GDF9, an essential factor for oogenesis, is under the control of MPC2, and acetylation of histone H4 in Nobox gene, another essential gene for oogenesis, and its expression are also controlled by MPC2. The results suggest that MPC2 is crucial for gene expression required during oogenesis by the histone modification via α-ketoglutarate.

Academic Significance and Societal Importance of the Research Achievements

本研究により、ミトコンドリア代謝がエピジェネティック制御を介して、卵胞形成に重要な役割を果たす分子機構の一端が、初めて明らかになり、代謝-エピゲノム制御軸による卵子形成制御の新たなしくみを示した。この研究成果は、卵胞形成不全等の疾患の原因の１つとして、ミトコンドリア代謝を介したエピジェネティック異常が関与する可能性を示唆し、今後、Mpc2遺伝子変異の有無による不妊リスクの評価などの発展が期待できる。

Research Products

• [Journal Article] Identification of spermatogenesis-associated changes in DNA methylation induced by maternal exposure to chemicals in male germ cells (2022)
  • Author(s): Yukiko Tando, Yasuhisa Matsui
  • Journal Title: Star Protocols Volume: 4 Issue: 4 Pages: 101912-101912
  • DOI: 10.1016/j.xpro.2022.101912
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic Control of Germline Formation and Differentiation in Mammals (2022)
  • Author(s): Hayashi Yohei、Matsui Yasuhisa
  • Journal Title: Sexual Development Volume: 27 Issue: 5-6 Pages: 1-16
  • DOI: 10.1159/000520662
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic pathways regulating the development and non-genomic heritable traits of germ cells (2022)
  • Author(s): MATSUI Yasuhisa、HAYASHI Yohei
  • Journal Title: Journal of Reproduction and Development Volume: 68 Issue: 2 Pages: 96-103
  • DOI: 10.1262/jrd.2021-137
  • NAID: 130008134310
  • ISSN: 0916-8818, 1348-4400
  • Peer Reviewed / Open Access
• [Journal Article] Abnormal early folliculogenesis due to impeded pyruvate metabolism in mouse oocytes. (2021)
  • Author(s): Tanaka, K., Hayashi, Y., Takehara, A., Ito-Matsuoka, Y., Tachibana, M., Yaegashi, N., Matsui, Y.
  • Journal Title: Biology of Reproduction Volume: 105 Issue: 1 Pages: 64-75
  • DOI: 10.1093/biolre/ioab064
  • Peer Reviewed
• [Journal Article] Epi-mutations for spermatogenic defects by maternal exposure to Di (2-ethylhexyl) phthalate (2021)
  • Author(s): Yukiko Tando, Hitoshi Hiura, Asuka Takehara, Yumi Ito-Matsuoka, Takahiro Arima, Yasuhisa Matsui
  • Journal Title: bioRxiv Volume: 1 Pages: 1-36
  • DOI: 10.1101/2021.05.19.444770
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptomic analysis reveals differences in the regulation of amino acid metabolism in asexual and sexual planarians (2019)
  • Author(s): Sekii Kiyono, Yorimoto Shunta, Okamoto Hikaru, Nagao Nanna, Maezawa Takanobu, Matsui Yasuhisa, Yamaguchi Katsushi, Furukawa Ryohei, Shigenobu Shuji, Kobayashi Kazuya
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 6132-6132
  • DOI: 10.1038/s41598-019-42025-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Shortened G1 phase of cell cycle and decreased histone H3K27 methylation are associated with AKT-induced enhancement of primordial germ cell reprogramming. (2019)
  • Author(s): Takehara, A., Mtasui, Y.
  • Journal Title: Development Growth and Differentiation Volume: 61 Issue: 6 Pages: 357-364
  • DOI: 10.1111/dgd.12621
  • Peer Reviewed
• [Journal Article] Comprehensive analysis of mouse CTA functions in cancer cells and roles of TEKT5 in cancer cells and testicular germ cells. (2019)
  • Author(s): Aoki, N., Matsui, Y.
  • Journal Title: Molecular and Cellular Biology Volume: 39 Issue: 17
  • DOI: 10.1128/mcb.00154-19
  • Peer Reviewed
• [Presentation] Epigenetic and metabolic controls in germ cell development (2022)
  • Author(s): Y.Matsui, Y.Tando, Y.Hayashi.
  • Organizer: The International Symposium ‘Totipotenmcy and germ cell development’
  • Int'l Joint Research / Invited
• [Presentation] 親の環境要因が仔の脳と精子形成に影響するしくみ (2022)
  • Author(s): 松居靖久、丹藤由希子、吉崎嘉一、有馬隆博、河野友宏、大隅典子
  • Organizer: 第６４回日本老年医学会学術集会
  • Invited
• [Presentation] Regulation of metabolic signaling in mouse primordial germ cell development. (2019)
  • Author(s): Y. Hayashi, K.Igarashi, A. Kanai, T, Soga, Y. Matsui.
  • Organizer: Cold Spring Harbor Meeting, 'Mechanisms of metabolic signaling'.
  • Int'l Joint Research
• [Presentation] Proteomic and metabolomic characterization in mouse fetal germline differentiation (2019)
  • Author(s): Yohei Hayashi, Keiko Tanaka, Masaru Mori, Kaori Igarashi, Akio Kanai, Tomoyoshi Soga, Nobuo Yaegashi, Yasuhisa Matsui
  • Organizer: 第42回日本分子生物学会年会
• [Remarks] 研究内容
  • URL: http://www2.idac.tohoku.ac.jp/dep/crcbr/kenkyu.html