Integrated analysis to understand the regulatory mechanism of neural stem cells by MIF

• Project/Area Number: 17K07115
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Keio University
• Principal Investigator: Ohta Shigeki 慶應義塾大学, 医学部(信濃町), 講師 (20365406)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: MIF / 神経幹細胞 / ZFHX4 / グリオーマ / グリオーマ幹細胞

Outline of Final Research Achievements

In this study, we newly identified a MIF signaling cascade, MIF-CHD7-TPT1-ZFHX4 in mouse NSPCs in vitro. In mouse embryonic brain, Zfhx4 was expressed in the ventricular zone of the cortex. Moreover, we generated a Zfhx4 knockout mouse using a Cas9 system. In Zfxh4 knockout fetal mouse, the number of Tbr2-positive cells in the cortex was decreased compared to wild type. In addition, ZFHX4 was highly expressed in glioma and regulated the cell proliferation of glioma cancer stem cells in vitro. Taken together, ZFHX4 may be a new candidate for a molecular targeting drug to treat glioma.

Academic Significance and Societal Importance of the Research Achievements

MIFがマウス神経幹細胞,ヒトES細胞由来神経幹細胞, グリオーマ幹細胞において、細胞増殖能を担うという発見を、その分子論的基盤を明らかにすることにより、より精緻なものとすることができた。とくに、MIF下流で新たに機能する因子として、ZFHX4を同定した。マウス胎児脳では、ヒト胎児脳同様に脳室周囲でのZFHX4の発現を見出した。ZFHX4が中間前駆細胞の発現制御を担うことが明らかとなったが、成体脳では海馬で発現することから、当該因子の高次脳機能における機能解明の重要性が明らかとなった。さらに、ZFHX4がグリオーマ幹細胞の細胞増殖に関わることから、治療薬開発に寄与する可能性が示された。

Research Products

• [Journal Article] Identification of KLRC2 as a candidate marker for brain tumor-initiating cells. (2019)
  • Author(s): Ishihara E, Takahashi S, Fukaya R, Ohta S, Yoshida K, Toda M.
  • Journal Title: Neurol Res. Volume: 41 Issue: 11 Pages: 1043-1049
  • DOI: 10.1080/01616412.2019.1672390
  • Peer Reviewed
• [Journal Article] CHARGE syndrome modeling using patient-iPSCs reveals defective migration of neural crest cells harboring CHD7 mutations (2017)
  • Author(s): Okuno H, Renault Mihara F, Ohta S, Fukuda K, Kurosawa K, Akamatsu W, Sanosaka T, Kohyama J, Hayashi K, Nakajima K, Takahashi T, Wysocka J, Kosaki K, Okano H.
  • Journal Title: elife Volume: 6 Pages: 23-24
  • DOI: 10.7554/elife.21114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Analysis of the regulatory mechanism underlying brain tumor-initiating cell proliferation by MIF (2019)
  • Author(s): Ohta S, Morimoto Y, Tokumitsu A, Sone T, Sakamoto A, Toda M, Kawakami Y, Okano H.
  • Organizer: Neuro2019
• [Presentation] Analysis of the regulatory mechanism underlying brain tumor-initiating cell proliferation by MIF (2019)
  • Author(s): Shigeki Ohta, Ayako Tokumitsu, Takafumi Sone, Ayuna Sakamoto, Yutaka Kawakami, Hideyuki Okano
  • Organizer: 第62回日本神経化学会大会・第42回日本神経科学大会
• [Presentation] MIF modulates the proliferation of neural stem/progenitors cells and glioma initiating cells (2018)
  • Author(s): Shigeki Ohta, Ayako Tokumitsu, Takafumi Sone, Ayuna Sakamoto, Yutaka Kawakami, Hideyuki Okano
  • Organizer: 第41回日本分子生物学会
• [Presentation] Functional analyses of TPT1 in neural stem/progenitor cells and glioma initiating cells. (2017)
  • Author(s): Ohta S, Okano H, Kawakami Y.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] TPT1 regulates the proliferation and/or survival of neural stem/progenitor cells and glioma stem cells. (2017)
  • Author(s): Ohta S, Tokumitsu A, Sone T, Sakamoto A, Kawakami Y, Okano H.
  • Organizer: 第60回日本神経化学会大会
• [Presentation] Functional analyses of TPT1 in neural stem/progenitor cells and glioma initiating cells. (2017)
  • Author(s): Ohta S, Kawakami Y, Okano H
  • Organizer: 2017 ISN-ESN meeting
  • Int'l Joint Research