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Establishment of sexual epigenome of germ cell via RNA-mediated mechanism

Planned Research

Project AreaAnalyses and regulation of germline epigenome
Project/Area Number 25112002
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionNational Institute of Genetics

Principal Investigator

Saga Yumiko  国立遺伝学研究所, 系統生物研究センター, 教授 (50221271)

Co-Investigator(Renkei-kenkyūsha) KATO Yuzuru  国立遺伝学研究所, 系統生物研究センター, 助教 (60570249)
AJIMA Rieko  国立遺伝学研究所, 系統生物研究センター, 助教 (10615066)
NINOMIYA Yoichirou  国立遺伝学研究所, 系統生物研究センター, 特任研究員 (90237777)
SUZUKI Atsushi  横浜国立大学, 工学(系)研究科(研究院), 准教授 (60467058)
Project Period (FY) 2013-06-28 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥140,920,000 (Direct Cost: ¥108,400,000、Indirect Cost: ¥32,520,000)
Fiscal Year 2017: ¥27,300,000 (Direct Cost: ¥21,000,000、Indirect Cost: ¥6,300,000)
Fiscal Year 2016: ¥27,430,000 (Direct Cost: ¥21,100,000、Indirect Cost: ¥6,330,000)
Fiscal Year 2015: ¥27,300,000 (Direct Cost: ¥21,000,000、Indirect Cost: ¥6,300,000)
Fiscal Year 2014: ¥36,530,000 (Direct Cost: ¥28,100,000、Indirect Cost: ¥8,430,000)
Fiscal Year 2013: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Keywords生殖細胞 / 性分化 / RNA制御 / Nanos2 / Stra8 / ES細胞 / キメラ解析 / DND1 / SMAD4 / Smad4 / 精子形成 / 幹細胞
Outline of Final Research Achievements

We found that the TGF-b signaling system, especially the Nodal/activin-SMAD2 pathway, works upstream of Nanos2, an RNA binding protein essential for germ cell male differentiation. On the other hand, we found that the BMP-SMAD4 pathway is important for female differentiation. We showed that removal of two factors, Stra8 and SMAD4 in female germ cells resulted in induction of prospermatogonia, even in the ovary. Based on this finding, we proposed that an unexpected model that testis-specific inducers are not essential for the determination of maleness in germ cells. We demonstrated that RNA binding protein DND1, a partner protein of Nanos2, is essential for recognition and binding of Nanos2 target RNA.

Report

(6 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (54 results)

All 2018 2017 2016 2015 2014 2013

All Journal Article (13 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 13 results,  Acknowledgement Compliant: 6 results,  Open Access: 6 results) Presentation (41 results) (of which Int'l Joint Research: 18 results,  Invited: 13 results)

  • [Journal Article] NANOS2 acts as an intrinsic regulator of gonocytes-to-spermatogonia transition in the murine testes.2018

    • Author(s)
      Pui HP, Saga Y.
    • Journal Title

      Mech Dev

      Volume: 149 Pages: 27-40

    • DOI

      10.1016/j.mod.2018.01.001

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gonocytes-to-spermatogonia transition initiates prior to birth in murine testes and it requires FGF signaling.2017

    • Author(s)
      Pui HP, Saga Y.
    • Journal Title

      Mech Dev.

      Volume: 印刷中 Pages: 125-139

    • DOI

      10.1016/j.mod.2017.03.002

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] NEDD4 controls spermatogonial stem cell homeostasis and stress response by regulating messenger ribonucleoprotein complexes.2017

    • Author(s)
      Zhou Z, Kawabe H, Suzuki A, Shinmyozu K, Saga Y.
    • Journal Title

      Nature Communication.

      Volume: 8 Issue: 1 Pages: 15662-15662

    • DOI

      10.1038/ncomms15662

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Roles of MIWI, MILI and PLD6 in small RNA regulation in mouse growing oocytes.2017

    • Author(s)
      Kabayama Y, Toh H, Katanaya A, Sakurai T, Chuma S, Kuramochi-Miyagawa S, Saga Y, Nakano T, Sasaki
    • Journal Title

      Nucleic Acids Res.

      Volume: 印刷中 Pages: 5387-5398

    • DOI

      10.1093/nar/gkx027

    • NAID

      120006355769

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sexual Fate Change of XX Germ Cells Caused by the Deletion of SMAD4 and STRA8 Independent of Somatic Sex Reprogramming.2016

    • Author(s)
      Wu Q, Fukuda K, Kato Y, Zhou Z, Deng CX, Saga Y
    • Journal Title

      PLoS Bio

      Volume: 14(9) Issue: 9 Pages: e1002553-e1002553

    • DOI

      10.1371/journal.pbio.1002553

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Dead end1 is an essential partner of NANOS2 for selective binding of target RNAs in male germ cell development.2016

    • Author(s)
      Suzuki A, Niimi Y, Shinmyozu K, Zhou Z, Kiso M, Saga Y.
    • Journal Title

      EMBO Rep.

      Volume: 17(1) Issue: 1 Pages: 37-46

    • DOI

      10.15252/embr.201540828

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Dazl is a target RNA suppressed by mammalian NANOS2 in sexually differentiating male germ cells2016

    • Author(s)
      Yuzuru Kato, Takeo Katsuki, Hiroki Kokubo, Aki Masuda, Yumiko Saga
    • Journal Title

      Nature Communications

      Volume: 7 Issue: 1 Pages: 1-11

    • DOI

      10.1038/ncomms11272

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The RNA binding protein Nanos2 organizes a post-transcriptional buffering system to retain primitive state of mouse spermatogonial stem cells.2015

    • Author(s)
      Zhi Zhou, Takayuki Shirakawa, Kazuyuki Ohbo, Aiko Sada, Quan Wu, Kazuteru Hasegawa, Rie Saba, Yumiko Saga
    • Journal Title

      Developmental Cell

      Volume: 34 Issue: 1 Pages: 96-107

    • DOI

      10.1016/j.devcel.2015.05.014

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] TALEN-Mediated Gene Disruption on Y Chromosome Reveals Critical Role of EIF2S3Y in Mouse Spermatogenesis2015

    • Author(s)
      Matsubara Yohei, Kato Tomoko, Kashimada Kenichi, Tanaka Hiromitsu, Zhi Zhou, Ichinose Shizuko, Mizutani Shuki, Morio Tomohiro, Chiba Tomoki, Ito Yoshiaki, Saga Yumiko, Takada Shuji, and Asahara Hiroshi
    • Journal Title

      Stem Cells and Development

      Volume: 24 Issue: 10 Pages: 1164-1170

    • DOI

      10.1089/scd.2014.0466

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] SMAD2 and p38 signaling pathways act in concert to determine XY primordial germ cell fate in mice.2015

    • Author(s)
      Wu Q, Fukuda K, Weinstein M, Graff JM, Saga Y.
    • Journal Title

      Development

      Volume: 142 Issue: 3 Pages: 575-586

    • DOI

      10.1242/dev.119446

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] CYP26B1 promotes male germ cell differentiation by suppressing STRA8-dependent meiotic and STRA8-independent mitotic pathways2014

    • Author(s)
      Saba R, Wu Q, Saga Y
    • Journal Title

      Dev Biol

      Volume: 389 Issue: 2 Pages: 173-81

    • DOI

      10.1016/j.ydbio.2014.02.013

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] FGF8-FGFR1 signaling acts as a niche factor for maintaining undifferentiated spermatogonia in the mouse.2014

    • Author(s)
      Hasegawa K, Saga Y.
    • Journal Title

      Biol Reprod.

      Volume: 91 Issue: 6 Pages: 145-145

    • DOI

      10.1095/biolreprod.114.121012

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Interaction of NANOS2 and NANOS3 with different components of the CNOT complex may contribute to the functional differences in mouse male germ cells.2014

    • Author(s)
      Suzuki A, Niimi Y, Saga Y.
    • Journal Title

      Biol Open.

      Volume: 3 Issue: 12 Pages: 1207-16

    • DOI

      10.1242/bio.20149308

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] Toward understanding the molecular mechanism of sexual fate decision in murine germ cells2018

    • Author(s)
      Yumiko Saga
    • Organizer
      日本発生生物学会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Role of Nanos Proteins in Male Germ Cell Development2017

    • Author(s)
      Yumiko Saga
    • Organizer
      Gordon Research Conference
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Primordial follicle formation: insights from a study of an RNA-binding protein.2017

    • Author(s)
      Yuzuru Kato
    • Organizer
      Gordon Research Conference
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Role of DDX6-mediated P-body formation in male germ cell development.2017

    • Author(s)
      Ryuki Shimada
    • Organizer
      Gordon Research Conference
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Post-transcriptional suppression of Dazl via its 3’UTR plays an important role in pre-implantation embryonic development.2017

    • Author(s)
      Kurumi Fukuda
    • Organizer
      Gordon Research Conference
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Egg or sperm: how germ cell sex is determined.2017

    • Author(s)
      Yumiko Saga
    • Organizer
      The International Research Symposium on Regulation of Germ cell Development in vivo and in vitro
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Primordial follicles: insights from a study of RNA-binding proteins for its development and activation2017

    • Author(s)
      Yuzuru Kato
    • Organizer
      The International Research Symposium on Regulation of Germ cell Development in vivo and in vitro
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Role of DDX6-mediated P-body formation in NANOS2 functio2017

    • Author(s)
      Ryuki Shimada
    • Organizer
      The International Research Symposium on Regulation of Germ cell Development in vivo and in vitro
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Requirement of DDX6-mediated P-body formation in male germ cell development2017

    • Author(s)
      Ryuki Shimada
    • Organizer
      日本発生生物学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Post-transcriptional suppression of Dazl via its 3’UTR plays an important role in pre-implantation embryonic development.2017

    • Author(s)
      Kurumi Fukuda
    • Organizer
      日本発生生物学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 生殖細胞特異的NANOS2-DND1経路の体細胞における再構成2017

    • Author(s)
      Takamasa Hirano
    • Organizer
      日本分子生物学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] マウス生殖細胞分化に必須なRNA結合タンパク質の機能を司る構造基盤の解析2017

    • Author(s)
      Danelle Wright
    • Organizer
      日本分子生物学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Germ cell-specific conditional KO via Cas9-mediated chimera analyses2017

    • Author(s)
      Yumiko Saga
    • Organizer
      The 20th US-Japan Cellular and Gene Therapy Conference
    • Place of Presentation
      FDA White Oak Campus, Maryland, USA
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Egg or sperm: which is the default?2016

    • Author(s)
      Yumiko Saga
    • Organizer
      The Allied Genetics Conference
    • Place of Presentation
      Orland, Florida, USA
    • Year and Date
      2016-07-13
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Role of a 3’UTR-dependent DAZL suppression in mouse postnatal ovary.2016

    • Author(s)
      Kurumi Fukuda, Yumiko Saga,
    • Organizer
      Mouse molecular genetics, The Allied Genetics Conference sponsored by the Genetics Society of America (GSA)
    • Place of Presentation
      Orland, Florida, USA
    • Year and Date
      2016-07-13
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Sex determination of mouse germ cells.2016

    • Author(s)
      Yumiko Saga.
    • Organizer
      International Symposium on Epigenetic Dynamics and Regulation in Germ Cells.
    • Place of Presentation
      kyoto
    • Year and Date
      2016-02-17
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Functional analyses of Nanos3 in mouse spermatogenesis.2016

    • Author(s)
      Takayuki Sakurai, Yumiko Saga.
    • Organizer
      International Symposium on Epigenetic Dynamics and Regulation in Germ Cells.
    • Place of Presentation
      Kyoto,
    • Year and Date
      2016-02-17
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Intrinsic regulation of the timing of gonocytes-to spermatogonia transition in the murine testes by an RNA-binding Protein NANOS2.2016

    • Author(s)
      Han Pin Pui and Yumiko Saga.
    • Organizer
      International Symposium on Epigenetic Dynamics and Regulation in Germ Cells.
    • Place of Presentation
      Kyoto
    • Year and Date
      2016-02-17
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] RNA制御を介した精子幹細胞の恒常性維持機構2016

    • Author(s)
      相賀裕美子、周智
    • Organizer
      日本分子生物学会
    • Place of Presentation
      横浜
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Role of post transcriptional suppression of Dazl via its 3’UTR in female reproduction2016

    • Author(s)
      Kurumi Fukuda, Yumiko Saga
    • Organizer
      日本発生生物学会Special Symposium
    • Place of Presentation
      Orland, Florida, USA
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] An intrinsic buffering mechanism in spermatogonial stem cells controls the timing of mouse spermatogenesis.2015

    • Author(s)
      Yumiko Saga. Zhi Zhou.
    • Organizer
      第38回日本分子生物学会年会・第88回日本生化学会大会合同大会(BMB2015).
    • Place of Presentation
      神戸
    • Year and Date
      2015-12-03
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Functional analyses of Nanos3 in mouse spermatogenesis.2015

    • Author(s)
      Takayuki Sakurai, Yumiko Saga.
    • Organizer
      第38回日本分子生物学会年会・第88回日本生化学会大会合同大会(BMB2015)
    • Place of Presentation
      神戸
    • Year and Date
      2015-12-03
    • Related Report
      2015 Annual Research Report
  • [Presentation] マウス卵形成における3'UTRを介したDazl発現抑制の役割2015

    • Author(s)
      福田胡桃、加藤譲、鈴木敦、相賀裕美子
    • Organizer
      第38回日本分子生物学会年会・第88回日本生化学会大会合同大会(BMB2015)
    • Place of Presentation
      神戸
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] Intrinsic regulation of the timing of gonocytes-to spermatogonia transition in the murine testes by an RNA-binding Protein NANOS2.2015

    • Author(s)
      Han Pin Pui and Yumiko Saga.
    • Organizer
      Mouse Molecular Genetics,
    • Place of Presentation
      Hinxton
    • Year and Date
      2015-09-19
    • Related Report
      2015 Annual Research Report
  • [Presentation] Functional analyses of Nanos3 in mouse spermatogenesis.2015

    • Author(s)
      Takayuki Sakurai, Yumiko Saga.
    • Organizer
      第48回日本発生生物学会
    • Place of Presentation
      つくば
    • Year and Date
      2015-06-02
    • Related Report
      2015 Annual Research Report
  • [Presentation] Mechanism of Sex determination of mouse germ cells2015

    • Author(s)
      Yumiko Saga
    • Organizer
      Vertebrate Sex determination meeting
    • Place of Presentation
      Kona hawaii
    • Year and Date
      2015-04-17
    • Related Report
      2014 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Sex determination of mouse germ cell2015

    • Author(s)
      Yumiko Saga
    • Organizer
      Finnish-Japanese joint symposium
    • Place of Presentation
      Helsinki
    • Year and Date
      2015-03-03
    • Related Report
      2014 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] he role of FGF signaling in the initiation and maintenance of murine spermatogenesis.2014

    • Author(s)
      Han Pin Pui, Yumiko Saga.
    • Organizer
      第37回日本分子生物学会,
    • Place of Presentation
      横浜
    • Year and Date
      2014-11-25
    • Related Report
      2014 Annual Research Report
  • [Presentation] Functional analyses of Nanos3 in mouse spermatogenesis.2014

    • Author(s)
      Takayuki Sakurai,Yumiko Saga.
    • Organizer
      第37回日本分子生物学会,
    • Place of Presentation
      横浜
    • Year and Date
      2014-11-25
    • Related Report
      2014 Annual Research Report
  • [Presentation] anos2 antagonizes dazl to achieve sexual differentiation of male germ cells in mouse embryos2014

    • Author(s)
      Yuzuru Kato,Yumiko Saga
    • Organizer
      CSH-GERM CELLS meeting
    • Place of Presentation
      NY
    • Year and Date
      2014-10-07
    • Related Report
      2014 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Female to male sex reversal of mouse PGCs independent of somatic environment.2014

    • Author(s)
      Quan Wu,Yumiko Saga.
    • Organizer
      CSH-GERM CELLS meeting
    • Place of Presentation
      NY
    • Year and Date
      2014-10-07
    • Related Report
      2014 Annual Research Report
    • Int'l Joint Research
  • [Presentation] anos2 organizes a post-transcriptional buffering system in mouse Spermatogonia Stem Cells2014

    • Author(s)
      Zhou Zhi,Yumiko Saga
    • Organizer
      第47回発生生物学会,
    • Place of Presentation
      NY
    • Year and Date
      2014-10-07
    • Related Report
      2014 Annual Research Report
  • [Presentation] Nanos2 organizes a post-transcriptional buffering system in mouse Spermatogonia Stem Cells.2014

    • Author(s)
      Zhou Zhi,Yumiko Saga
    • Organizer
      第47回発生生物学会
    • Place of Presentation
      名古屋 (WINC AICHI)
    • Year and Date
      2014-05-28
    • Related Report
      2013 Annual Research Report
  • [Presentation] Identification of a Nanos2 target in the mouse male germ cells2014

    • Author(s)
      Yuzuru,Kato.,Yumiko,Saga.
    • Organizer
      第46回 日本発生生物学会
    • Place of Presentation
      名古屋 (WINC AICHI)
    • Year and Date
      2014-05-28
    • Related Report
      2013 Annual Research Report
  • [Presentation] A revised model of gonocytes-to-spermatogonia transition in the mouse testis.2014

    • Author(s)
      Han Pin Pui,Yumiko Saga.
    • Organizer
      第47回発生生物学会
    • Place of Presentation
      名古屋
    • Year and Date
      2014-05-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] Germ cell sexual differentiation requires Nanos2-mediated dosage control of Dazl in mice2014

    • Author(s)
      Yuzuru Kato,Yumiko Saga.
    • Organizer
      第47回発生生物学会
    • Place of Presentation
      名古屋
    • Year and Date
      2014-05-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] Smad2 and p38 signaling orchestrate the male fate decision of mouse PGC.2014

    • Author(s)
      Quan Wu,Yumiko Saga.
    • Organizer
      第47回発生生物学会,
    • Place of Presentation
      名古屋
    • Year and Date
      2014-05-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] Suppression of pluripofency gene together with NANOS2 is essential for male sexual differentiation in mouse germ cells.2014

    • Author(s)
      Hiroko Koike, Yumiko Saga.
    • Organizer
      第47回発生生物学会,
    • Place of Presentation
      名古屋
    • Year and Date
      2014-05-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] Germ cell specific factors, NANOS2 and NANOS3 interact with distinct components of the CNOT complex2013

    • Author(s)
      相賀裕美子
    • Organizer
      第36回日本分子生物学会
    • Place of Presentation
      神戸(ポートアイランド)
    • Year and Date
      2013-12-04
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Uncovering a role of Nanos2 in sexual differentiation of murine male germ cells2013

    • Author(s)
      Yuzuru Kato, Yumiko Saga,
    • Organizer
      Mouse molecular Genetics
    • Place of Presentation
      Hinxton (英国)Wellcome Trust Genome Campus
    • Year and Date
      2013-09-18 – 2013-09-21
    • Related Report
      2013 Annual Research Report
  • [Presentation] Maintenance of spermatogonial stem cell(SSCs) via Nanos2-mediated mechanism.2013

    • Author(s)
      相賀裕美子
    • Organizer
      第86回日本生化学会
    • Place of Presentation
      横浜 (パシフィコ横浜)
    • Year and Date
      2013-09-11
    • Related Report
      2013 Annual Research Report
    • Invited

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Published: 2013-07-10   Modified: 2019-03-29  

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