Analysis of MCPH genes in mice with induced outer radial glia

• Project/Area Number: 18K14828
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Fujita Ikumi 国立研究開発法人理化学研究所, 生命機能科学研究センター, 研究員 (80615138)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 小頭症 / Aspm / oRG / OSVZ / 細胞分裂 / 染色体分配 / 神経幹細胞 / アポトーシス / 紡錘体 / CRISPR/Cas9 / LGN / 紡錘体角度 / 接着結合 / 神経発生 / 大脳皮質 / outer radial glia / LGN/Gpsm2 / 外脳室下帯

Outline of Final Research Achievements

In this study, we showed that the loss of the Aspm function causes chromosome mis-segregation in the developing cortex, which increases cell death and decreases brain size. Cell death by the Aspm mutation was increased by artificial induction of oRG by using the LGN mutant mice, suggesting that developing scheme with oRG is susceptible to the spindle malformation by the Aspm mutation. Increase of cell death by the oRG induction was observed during the mid and late neurogenic stages. We revealed that induction of oRG is repressed by the regeneration ability of the epithelial structure in neural stem cells during the proliferative to early neurogenic stages.

Academic Significance and Societal Importance of the Research Achievements

Aspm遺伝子変異は，ヒトでは重篤な小頭症を引き起こすものの，マウスにおいてはわずかな表現型しか示さないことから，モデル動物を用いた小頭症の研究には困難が伴っていた。本研究では，LGN変異マウスを用いて人工的にoRG幹細胞を誘導することでAspm変異が重篤な小頭症を引き起こす現象を発見し，小頭症の発症機序を解明するために有用なモデル系であることを示した点で意義がある。また，oRGの発生時期特異的な誘導機構の研究を通して，神経幹細胞が発生初期には形態再生能を持つことを発見し，脳発生研究に新たな視点をもたらした。

Research Products

• [Journal Article] Endfoot regeneration restricts radial glial state and prevents translocation into the outer subventricular zone in early mammalian brain development (2019)
  • Author(s): Fujita Ikumi、Shitamukai Atsunori、Kusumoto Fumiya、Mase Shun、Suetsugu Taeko、Omori Ayaka、Kato Kagayaki、Abe Takaya、Shioi Go、Konno Daijiro、Matsuzaki Fumio
  • Journal Title: Nature Cell Biology Volume: 22 Issue: 1 Pages: 26-37
  • DOI: 10.1038/s41556-019-0436-9
  • Peer Reviewed / Open Access
• [Journal Article] Reconstruction of Par-dependent polarity in apolar cells reveals a dynamic process of cortical polarization (2019)
  • Author(s): Kono K, Yoshiura S, Fujita I, Okada Y, Shitamukai A, Shibata T, Matsuzaki F
  • Journal Title: eLife Volume: 8 Pages: 1-31
  • DOI: 10.7554/elife.45559
  • NAID: 120006653006
  • Peer Reviewed / Open Access
• [Journal Article] 哺乳類の発生期大脳における神経幹細胞の形態的恒常性 (2018)
  • Author(s): 藤田 生水, 松崎 文雄
  • Journal Title: 細胞 Volume: 50 Pages: 375-378
• [Presentation] Regeneration of the epithelial structure in neural stem cells during mammalian brain development (2020)
  • Author(s): Fujita I, Shitamukai A, Kusumoto F, Mase S, Suetsugu T, Omori A, Kato K, Abe T, Shioi G, Konno D, Matsuzaki F
  • Organizer: Cell Bio Virtual 2020 Meeting (ASCB)
  • Int'l Joint Research
• [Presentation] Regeneration ability of the epithelial structure in neural stem cells during mammalian brain development (2020)
  • Author(s): Fujita I, Shitamukai A, Kusumoto F, Mase S, Suetsugu T, Omori A, Kato K, Abe T, Shioi G, Konno D, Matsuzaki F
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] Structural plasticity of neural stem cells in mammalian brain development (2019)
  • Author(s): Fujita I, Shitamukai A, Kusumoto F, Suetsugu T, Mase S, Kato K, Abe T, Shioi G, Konno D, Matsuzaki F
  • Organizer: Joint Annual Meeting of 71st JSCB & 19th PSSJ
• [Presentation] Regenerative plasticity of the epithelial structure in radial glia during the early mammalian brain development (2018)
  • Author(s): Ikumi Fujita, Atsunori Shitamukai, Fumiya Kusumoto, Shun Mase, Taeko Suetsugu, Daijiro Konno, Fumio Matsuzaki
  • Organizer: ASCB | EMBO 2018 Meeting
  • Int'l Joint Research
• [Presentation] Induction of outer radial glia causes severe microcephaly in the Aspm mutant mice (2018)
  • Author(s): Ikumi Fujita, Taeko Suetsugu, Chiaki Kishida, Yuji Tsunekawa, Daijiro Konno, Akira Fujimori, Fumio Matsuzaki
  • Organizer: 22nd Biennial Meeting of the ISDN
  • Int'l Joint Research
• [Remarks] RIKEN Research News
  • URL: https://www.riken.jp/en/news_pubs/research_news/rr/202000313_2/index.html