Mechanism of female germ cell fate determination by a transcription factor ZGLP1

• Project/Area Number: 20K15801
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 44020:Developmental biology-related
• Research Institution: Nara Medical University
• Principal Investigator: Nagaoka So 奈良県立医科大学, 医学部, 助教 (20870158)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 卵形成 / 不妊症 / 早発卵巣不全 / 減数分裂 / 始原生殖細胞 / 試験管内分化誘導 / ZGLP1 / 配偶子形成 / 試験管内誘導 / 相同組換え / レトロトランスポゾン抑制 / 生殖寿命 / 性決定 / 転写制御 / 相同組換え形成 / 多能性幹細胞 / 卵母細胞 / 転写制御機構

Outline of Research at the Start

卵母細胞は、次世代個体を形成しうる能力を有する生命継承の担い手であり、始原生殖細胞を起源として、胎生期に生殖巣体細胞からのシグナルによって運命決定される。申請者は最近、多能性幹細胞から始原生殖細胞を試験管内再構成する実験系を用いて、転写因子ZGLP1を強制発現させると90%以上の効率で卵母細胞への分化が誘導されることを発見した。本研究では液性因子との上流・下流関係や直接の標的因子の同定を含む、ZGLP1による卵母細胞の運命決定機構を解明する。

Outline of Final Research Achievements

Oocytes possess the ability to create all cell types in the body and thus are the keystone for assuring species’ continuation. In this research project, we aimed to elucidate the mechanisms by which ZGLP1, an evolutionarily conserved transcription factor, induces female sex differentiation in developing germ cells. With the use of in vitro germ cell derivation technology, we conducted detailed transcriptome analyses during fetal and neonatal oogenesis. We identified new factors that play pivotal roles in the assurance of oocyte survival through, for example, the regulations of meiotic progression and cellular homeostasis. Our findings advanced the understanding of how ovarian reserve is established and maintained. Additionally, our work provides clues on how to establish human in vitro gametogenesis in the future.

Academic Significance and Societal Importance of the Research Achievements

女性の生涯における生殖能力は卵母細胞の「数」と「質」が胎児期に正しく作られることによって保証されるが、胎児期の卵母細胞形成を制御するプログラムの多くは不明瞭である。本研究により胎児期卵母細胞の生存を保証する転写プログラムの理解を向上することができ、女性の妊孕性を規定する卵巣予備能成立の根底プロセスの理解が進んだ。この成果は、不妊症の機序の理解に貢献し、また、将来的なヒト卵母細胞の試験管内誘導の創出にも寄与すると期待できる。

Research Products

• [Int'l Joint Research] The Barcelona Inst. of Sci. and Tech.(スペイン)
• [Int'l Joint Research] Universite de Montpelier(フランス)
• [Journal Article] Controlled X‐chromosome dynamics defines meiotic potential of female mouse <i>in vitro</i> germ cells (2022)
  • Author(s): Severino Jacqueline、Bauer Moritz、Mattimoe Tom、Arecco Niccolo、Cozzuto Luca、Lorden Patricia、Hamada Norio、Nosaka Yoshiaki、Nagaoka So I、Audergon Pauline、Tarruell Antonio、Heyn Holger、Hayashi Katsuhiko、Saitou Mitinori、Payer Bernhard
  • Journal Title: The EMBO Journal Volume: 41 Issue: 12 Pages: 1-23
  • DOI: 10.15252/embj.2021109457
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DMRT1-mediated reprogramming drives development of cancer resembling human germ cell tumors with features of totipotency (2021)
  • Author(s): Taguchi Jumpei、Shibata Hirofumi、Kabata Mio、Kato Masaki、Fukuda Kei、Tanaka Akito、Ohta Sho、Ukai Tomoyo、Mitsunaga Kanae、Yamada Yosuke、Nagaoka So I、Yamazawa Sho、Ohnishi Kotaro、Woltjen Knut、Ushiku Tetsuo、Ozawa Manabu、Saitou Mitinori、Shinkai Yoichi、Yamamoto Takuya、Yamada Yasuhiro
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 5041-5041
  • DOI: 10.1038/s41467-021-25249-4
  • Peer Reviewed / Open Access
• [Journal Article] Reconstituting oogenesis in vitro: recent progress and future prospects (2021)
  • Author(s): Nagaoka So I.、Saitou Mitinori、Kurimoto Kazuki
  • Journal Title: Current Opinion in Endocrine and Metabolic Research Volume: 18 Pages: 145-151
  • DOI: 10.1016/j.coemr.2021.03.022
  • Peer Reviewed
• [Journal Article] ZGLP1 is a determinant for the oogenic fate in mice (2020)
  • Author(s): Nagaoka So I.、Nakaki Fumio、Miyauchi Hidetaka、Nosaka Yoshiaki、Ohta Hiroshi、Yabuta Yukihiro、Kurimoto Kazuki、Hayashi Katsuhiko、Nakamura Tomonori、Yamamoto Takuya、Saitou Mitinori
  • Journal Title: Science Volume: 367 Issue: 6482 Pages: 4115-4115
  • DOI: 10.1126/science.aaw4115
  • NAID: 120006850276
  • Peer Reviewed / Int'l Joint Research
• [Presentation] in vitro 卵母細胞誘導系を用いた減数分裂制御機構の解析 (2021)
  • Author(s): 長岡創
  • Organizer: 国立遺伝学研究所研究会「染色体安定維持研究会」
• [Presentation] Reconstitution of oogenic processes from pluripotent stem cells (2020)
  • Author(s): Nagaoka So I.
  • Organizer: 第４３回日本分子生物学会年会