Identification of the molecule basis on Hes1 oscillation that contributes to the heterogeneous differentiation of stem cells.

• Project/Area Number: 22687017
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Developmental biology
• Research Institution: Kyoto University
• Principal Investigator: KOBAYASHI Taeko 京都大学, ウイルス研究所, 助教 (40402804)
• Project Period (FY): 2010-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥25,610,000 (Direct Cost: ¥19,700,000、Indirect Cost: ¥5,910,000); Fiscal Year 2013: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2012: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2011: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000); Fiscal Year 2010: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
• Keywords: Hes1 / オシレーション / 幹細胞分化 / ES細胞 / 転写因子 / 翻訳後修飾 / ユビキチン化 / 不均一性

Research Abstract

Embryonic stem (ES) cells display heterogeneous responses upon induction of differentiation. We have shown that Hes1 expression oscillates in mouse ES cells and that this oscillating expression contributes to the heterogeneous responses. We found the following three results supported by this grant. 1. We found that Hes1 acts as an inhibitor but not as an effector of Notch signaling in ES cell differentiation and that sustained Hes1 expression promotes the preference for the mesodermal rather than the neural fate by suppression of Notch signaling. 2. We found that Hes1 depletion enhances the neural differentiation in both human ES and iPS cell lines as well as mouse ES cell lines. 3. We searched new regulators of Hes1 oscillation from affinity-purified proteins with Hes1 from mouse ES cells and found that the deubiquitinases stabilize Hes1 protein via removing ubiquitin molecules from Hes1, modulate Hes1 oscillation and regulate the neuronal differentiation of neural stem cells.

Research Products

• [Journal Article] Expression dynamics and functions of Hes genes in development and diseases (2014)
  • Author(s): 小林妙子, 影山龍一郎
  • Journal Title: Cur. Top. Dev. Biol Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Novel and robust transplantation reveals the acquisition of polarized processes by cortical cells derived from mouse and human pluripotent stem cells (2014)
  • Author(s): Nagashima F, Suzuki IK, Shitamukai A, Sakaguchi H, Iwashita M, Kobayashi T, Tone S, Toida K, Vanderhaeghen P, Kosodo Y
  • Journal Title: Stem Cells Dev Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] The roles and mechanism of ultradian oscillatory expression of the mouse Hes genes. (2014)
  • Author(s): Harima Y, Imayoshi I, Shimojo H, Kobayashi T, Kageyama R.
  • Journal Title: Semin Cell Dev Biol. Volume: 34 Pages: 85-90
  • DOI: 10.1016/j.semcdb.2014.04.038
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Expression dynamics and functions of Hes genes in development and diseases (2014)
  • Author(s): Taeko Kobayashi and Ryoichiro Kageyama
  • Journal Title: Current Topics in Developmental Biology Volume: in press
  • Peer Reviewed
• [Journal Article] Novel and Robust Transplantation Reveals the Acquisition of Polarized Processes by Cortical Cells Derived from Mouse and Human Pluripotent Stem Cells. (2014)
  • Author(s): Fumiaki Nagashima, Ikuo K. Suzuki, Atsunori Shitamukai, Haruko Sakaguchi, Misato Iwashita, Taeko Kobayashi, Shigenobu Tone, Kazunori Toida, Pierre Vanderhaeghen, and Yoichi Kosodo
  • Journal Title: Stem Cells and Development Volume: in press
  • Peer Reviewed
• [Journal Article] The role of Hes genes in intestinaldevelopment, homeostasis and tumorformation (2012)
  • Author(s): Ueo T, Imayoshi T, Kobayashi T, OhtsukaT, Seno H, Nakae H, Chiba T, Kageyama R
  • Journal Title: Development Volume: 139 Issue: 6 Pages: 1071-1082
  • DOI: 10.1242/dev.069070
  • Peer Reviewed
• [Journal Article] Hes1 oscillations contribute to heterogeneous differentiation responses in embryonic stem cells (2011)
  • Author(s): 小林妙子, 影山龍一郎
  • Journal Title: Genes Volume: Vol.2 Pages: 219-228
  • Peer Reviewed
• [Journal Article] Hes1 oscillations contribute to heterogeneous differentiation responses in embryonic stem cells. (2011)
  • Author(s): 小林妙子、影山龍一郎
  • Journal Title: Genes Volume: 2 Pages: 219-228
  • Peer Reviewed
• [Journal Article] Hesl regulates embryonic stem cell differentiation by suppressing Notch signaling (2010)
  • Author(s): Kobayashi, T. and Kageyama, R.
  • Journal Title: Genes to Cells Volume: 15 Issue: 7 Pages: 689-698
  • DOI: 10.1111/j.1365-2443.2010.01413.x
  • Peer Reviewed
• [Journal Article] Ultradian oscillations in Notch signaling regulate dynamic biological events (2010)
  • Author(s): 影山龍一郎, 丹羽康隆, 下條博美, 小林妙子, 大塚俊之
  • Journal Title: Curr. Top. Dev. Biol Volume: Vol.92 Pages: 311-331
  • DOI: 10.1016/s0070-2153(10)92010-3
  • ISBN: 9780123809148
  • Peer Reviewed
• [Journal Article] 幹細胞分化の運命決定に寄与するリズム現象 (2010)
  • Author(s): 小林妙子, 影山龍一郎
  • Journal Title: 医学のあゆみ Volume: Vol.235 Pages: 953-954
  • URL: http://www.ishiyaku.co.jp/magazines/ayumi/AyumiBookDetailNew.aspx?BC=923509
• [Journal Article] Hes1 regulates embryonic stem cell differentiation by suppressing Notch signaling (2010)
  • Author(s): 小林妙子、影山龍一郎
  • Journal Title: Genes to Cells Volume: 15 Pages: 689-698
  • Peer Reviewed
• [Journal Article] Ultradian oscillations in Notch signaling regulate dynamic biological events. (2010)
  • Author(s): 影山龍一郎、丹羽康隆、下條博美、小林妙子、大塚俊之
  • Journal Title: Curr.Top.Dev.Biol. Volume: 92 Pages: 311-331
  • Peer Reviewed
• [Journal Article] 幹細胞分化の運命決定に寄与するリズム現象 (2010)
  • Author(s): 小林妙子、影山龍一郎
  • Journal Title: 医学のあゆみ Volume: 235 Pages: 953-954
• [Presentation] 転写因子Hes1の発現振動によるES細胞の分化調節機構 (2011)
  • Author(s): 小林妙子
  • Organizer: 第18回日本時間生物学会シンポジウム「哺乳類の時計と振動原理」
  • Place of Presentation: 名古屋大学野依記念学術交流会館
  • Year and Date: 2011-11-25
  • Invited
• [Presentation] 転写因子Hes1の発現振動によるES細胞の分化調節機構 (2011)
  • Author(s): 小林妙子
  • Organizer: 第18回日本時間生物学会シンポジウム「哺乳類の時計と振動原理」
  • Place of Presentation: 名古屋大学野依記念学術交流会館(招待講演)
  • Year and Date: 2011-11-25
• [Presentation] 転写因子Hes1の発現振動によるES細胞の分化調節機構 (2011)
  • Author(s): 小林妙子
  • Organizer: 第8回「生物数学の理論とその応用」Theory of Biomathematics and Its Applications VIIIミニシンポジウム「リズムと生物学」
  • Place of Presentation: 京都大学数理解析研究所
  • Year and Date: 2011-11-17
  • Invited
• [Presentation] 転写因子Hes1の発現振動によるES細胞の分化調節機構 (2011)
  • Author(s): 小林妙子
  • Organizer: 第8回「生物数学の理論とその応用」Theory of Biomathematics and Its Applications VIIIミニシンポジウム「リズムと生物学」
  • Place of Presentation: 京都大学数理解析研究所(招待講演)
  • Year and Date: 2011-11-17
• [Presentation] 幹細胞について (2011)
  • Author(s): 小林妙子
  • Organizer: 臨床検査部会講演会(京都私立病院協会主催)
  • Place of Presentation: COCON烏丸8階京都私立病院協会会議室
  • Year and Date: 2011-02-03
  • Invited
• [Presentation] 幹細胞について (2011)
  • Author(s): 小林妙子
  • Organizer: 臨床検査部会講演会(京都私立病院協会主催)
  • Place of Presentation: COCON烏丸8階 京都私立病院協会会議室(招待講演)
  • Year and Date: 2011-02-03
• [Presentation] 振動遺伝子Hes1によるES細胞の分化調節機構 (2010)
  • Author(s): 小林妙子
  • Organizer: 理研シンポジウム「細胞システムの動態と論理II」
  • Place of Presentation: 独立行政法人理化学研究所・和光
  • Invited
• [Presentation] The cyclic gene Hes1 contribute s to diverse differentiation responses of mo use embryonic stem (ES) cells by regulating Notch signaling activation (2010)
  • Author(s): 小林妙子
  • Organizer: 第49回日本生体医工学会大会
  • Place of Presentation: 大阪国際交流センター
  • Invited
• [Presentation] 振動遺伝子Hes1はNotchシグナル制御を介してES細胞の多様な分化応答に寄与する (2010)
  • Author(s): 小林妙子
  • Organizer: Neuro 2010 (第33回日本神経科学大会・第53回日本神経科学会大会・第20回日本神経回路学会大会)
  • Place of Presentation: 神戸コンベンションセンター
• [Presentation] Hes1 contributes to diverse diffe rentiation responses of ES cells by regulatin g Notch signaling (2010)
  • Author(s): 小林妙子
  • Organizer: "TheNotchMeeting_2010" - Notch & Stem Cells 2010
  • Place of Presentation: Athens, Greece
• [Presentation] 転写因子Hes1の発現振動によるES細胞の分化調節機構 (2010)
  • Author(s): 小林妙子
  • Organizer: 定量生物学の会第3回年会
  • Place of Presentation: 東京大学生産技術研究所
  • Invited
• [Presentation] Hes1はNotchシグナルを抑制してES細胞の分化を制御する (2010)
  • Author(s): 小林妙子
  • Organizer: BMB2010(第33回日本分子生物学会年会・第83回日本生化学会大会合同大会)
  • Place of Presentation: 神戸ポートアイランド
• [Presentation] 振動遺伝子Hes1によるES細胞の分化調節機構 (2010)
  • Author(s): 小林妙子
  • Organizer: 理研シンポジウム「細胞システムの動態と論理 II」
  • Place of Presentation: 独立行政法人理化学研究所・和光(招待講演)
• [Presentation] The cyclic gene Hes1 contributes to diverse differentiation responses of mouse embryonic stem (ES) cells by regulating Notch signaling activation. (2010)
  • Author(s): 小林妙子
  • Organizer: 第49回日本生体医工学会大会
  • Place of Presentation: 大阪国際交流センター(招待講演)
• [Presentation] 振動遺伝子Hes1はNotchシグナル制御を介してES細胞の多様な分化応答に寄与する。(The cyclic gene Hes1 contributes to diverse differentiation responses of mouse embryonic stem (ES) cells by regulating Notch signaling activation.) (2010)
  • Author(s): 小林妙子
  • Organizer: Neuro 2010(第33回日本神経科学大会・第53回日本神経科学会大会・第20回日本神経回路学会大会)
  • Place of Presentation: 神戸コンベンションセンター
• [Presentation] Hes1 contributes to diverse differentiation responses of ES cells by regulating Notch signaling. (2010)
  • Author(s): 小林妙子
  • Organizer: "TheNotchMeeting_2010"-Notch & Stem Cells 2010
  • Place of Presentation: Athens, Greece
• [Presentation] 転写因子Hes1の発現振動によるES細胞の分化調節機構 (2010)
  • Author(s): 小林妙子
  • Organizer: 定量生物学の会 第3回年会
  • Place of Presentation: 東京大学生産技術研究所 コンベンションホール(招待講演)
• [Presentation] Hes1はNotchシグナルを抑制してES細胞の分化を制御する。(Hes1 regulates embryonic stem cell differentiation by suppressing Notch signaling) (2010)
  • Author(s): 小林妙子
  • Organizer: BMB2010(第33回日本分子生物学会年会・第83回日本生化学会大会 合同大会)
  • Place of Presentation: 神戸ポートアイランド
• [Book] 脳科学辞典 (2013)
  • Author(s): 小林妙子
  • Publisher: Hes ファミリー
  • URL: http://bsd.neuroinf.jp/wiki/Hes
• [Book] Hesファミリー (2013)
  • Author(s): 小林 妙子
  • Publisher: 脳科学辞典
• [Remarks]
  • URL: http://www.virus.kyoto-u.ac.jp/Lab/Kageyama/research_stemcell.html
• [Remarks]
  • URL: http://www.virus.kyoto-u.ac.jp/about/y2009/kageyama200908.html
• [Remarks] アウトリーチ活動サイエンスカフェ, 第15回 iCeMS(京都大学物質-細胞統合システム拠点)カフェ「リズムにのる細胞」
  • URL: http://www.icems.kyoto-u.ac.jp/j/rsch/scg/2013/08/21-cafe15report.html
• [Remarks] 研究内容ー幹細胞分化調節
  • URL: http://www.virus.kyoto-u.ac.jp/Lab/Kageyama/research_stemcell.html
• [Remarks] 京都大学ウイルス研究所 研究トピックス
  • URL: http://www.virus.kyoto-u.ac.jp/about/y2009/kageyama200908.html
• [Remarks] 京都大学ウイルス研究所 増殖制御学
  • URL: http://www.virus.kyoto-u.ac.jp/Lab/Kageyama/index.html
• [Remarks]
• [Remarks]
  • URL: http://www.virus.kyoto-u.ac.jp/about/y2009/kageyama200908.html
• [Remarks]
  • URL: http://www.virus.kyoto-u.ac.jp/Lab/Kageyama/research_stemcell.html
• [Remarks]
  • URL: http://www.virus.kyoto-u.ac.jp/about/y2009/kageyama200908.html
• [Patent(Industrial Property Rights)] 多能性幹細胞からの神経細胞の分化誘導方法 (2010)
  • Inventor(s): 小林妙子、影山龍一郎
  • Industrial Property Rights Holder: 京都大学
  • Filing Date: 2010-07-15
  • Overseas