Developmental mechanisms of the cerebral cortex in ferrets

• Project/Area Number: 18K19376
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 46:Neuroscience and related fields
• Research Institution: Kanazawa University
• Principal Investigator: Shinmyo Yohei 金沢大学, 医学系, 准教授 (00418831)
• Co-Investigator(Kenkyū-buntansha): 河崎 洋志 金沢大学, 医学系, 教授 (50303904)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 大脳皮質 / フェレット / 脳回 / Cdk5 / CRISPR/Cas9

Outline of Final Research Achievements

Folds in the cerebral cortex in mammals are believed to be key structures for accommodating increased cortical neurons in the cranial cavity. However, the mechanisms underlying cortical folding remain largely unknown. By combining in utero electroporation and the CRISPR/Cas9 system, we succeeded in efficient gene knockout of Cdk5, which is mutated in some patients with classical lissencephaly, in the gyrencephalic brains of ferrets. We show that Cdk5 knockout in the ferret cerebral cortex markedly impaired cortical folding. Furthermore, the results obtained from the introduction of dominant-negative Cdk5 into specific cortical layers suggest that Cdk5 function in upper-layer neurons is more important for cortical folding than that in lower-layer neurons. Cdk5 inhibition induced severe migration defects in cortical neurons. Taken together, our findings suggest that the appropriate positioning of upper-layer neurons is critical for cortical folding.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、脳回形成機構の解明のみならず、臨床脳医学にも大きく貢献できる。ヒト脳回形成異常に見られるてんかんや発達遅滞の発症メカニズムには不明な点が多く、根本的な治療法は確立されていないのが現状である。本研究成果は、脳回異常による脳機能障害の発症メカニズムの解明に繋がる有益な知見である。さらに、本研究で作成した脳回形成異常フェレットが、今後の治療法開発において有用なモデル動物になることも期待できる。

Research Products

• [Journal Article] Glial cell type-specific gene expression in the mouse cerebrum using the piggyBac system and in utero electroporation (2021)
  • Author(s): Hamabe-Horiike Toshihide、Kawasaki Kanji、Sakashita Masataka、Ishizu Chihiro、Yoshizaki Tomokazu、Harada Shin-ichi、Ogawa-Ochiai Keiko、Shinmyo Yohei、Kawasaki Hiroshi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 4864-4864
  • DOI: 10.1038/s41598-021-84210-z
  • Peer Reviewed / Open Access
• [Journal Article] The expression of aristaless-related homeobox in neural progenitors of gyrencephalic carnivore ferrets (2021)
  • Author(s): Maeyama Hiroki、Shinmyo Yohei、Kawasaki Hiroshi
  • Journal Title: Biochemistry and Biophysics Reports Volume: 26 Pages: 100970-100970
  • DOI: 10.1016/j.bbrep.2021.100970
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dysfunction of the proteoglycan Tsukushi causes hydrocephalus through altered neurogenesis in the subventricular zone in mice (2021)
  • Author(s): Ito Naofumi、(24/28)
  • Journal Title: Science Translational Medicine Volume: 13 Issue: 587 Pages: 7896-7896
  • DOI: 10.1126/scitranslmed.aay7896
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel third mesh-like myometrial layer connects the longitudinal and circular muscle fibers -A potential stratum to coordinate uterine contractions- (2020)
  • Author(s): Kagami Kyosuke, Ono Masanori, Iizuka Takashi, Matsumoto Takeo, Hosono Takashi, Sekizuka-Kagami Naomi, Shinmyo Yohei, Kawasaki Hiroshi, Fujiwara Hiroshi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 8274-8274
  • DOI: 10.1038/s41598-020-65299-0
  • Peer Reviewed / Open Access
• [Journal Article] A discrete subtype of neural progenitor crucial for cortical folding in the gyrencephalic mammalian brain (2020)
  • Author(s): Matsumoto Naoyuki、Tanaka Satoshi、Horiike Toshihide、Shinmyo Yohei、Kawasaki Hiroshi
  • Journal Title: eLife Volume: 9
  • DOI: 10.7554/elife.54873
  • Peer Reviewed / Open Access
• [Journal Article] The origin and development of subcortical U-fibers in gyrencephalic ferrets. (2020)
  • Author(s): Yoshino M, Saito K, Kawasaki K, Horiike T, Shinmyo Y, Kawasaki H.
  • Journal Title: Mol Brain Volume: 13 Issue: 1 Pages: 37-37
  • DOI: 10.1186/s13041-020-00575-8
  • Peer Reviewed / Open Access
• [Journal Article] Draxin-mediated Regulation of Granule Cell Progenitor Differentiation in the Postnatal Hippocampal Dentate Gyrus. (2020)
  • Author(s): Tawarayama H, Yamada H, Amin R, Morita-Fujimura Y, Cooper HM, Shinmyo Y, Tanaka H, Ikawa S.
  • Journal Title: Neuroscience Volume: 431 Pages: 184-192
  • DOI: 10.1016/j.neuroscience.2020.02.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Characterization of the Inner and Outer Fiber Layers in the Developing Cerebral Cortex of Gyrencephalic Ferrets. (2019)
  • Author(s): Saito K, Mizuguchi K, Horiike T, Dinh Duong TA, Shinmyo Y, Kawasaki H.
  • Journal Title: Cereb Cortex. Volume: 29 Issue: 10 Pages: 4303-4311
  • DOI: 10.1093/cercor/bhy312
  • Peer Reviewed
• [Journal Article] FGF Signaling Directs the Cell Fate Switch from Neurons to Astrocytes in the Developing Mouse Cerebral Cortex. (2019)
  • Author(s): Dinh Duong TA, Hoshiba Y, Saito K, Kawasaki K, Ichikawa Y, Matsumoto N, Shinmyo Y, Kawasaki H.
  • Journal Title: J Neurosci Volume: 39 Issue: 31 Pages: 6081-6094
  • DOI: 10.1523/jneurosci.2195-18.2019
  • Peer Reviewed
• [Journal Article] Three-dimensional evaluation of murine ovarian follicles using a modified CUBIC tissue clearing method. (2018)
  • Author(s): Kagami K., Shinmyo Y., Ono M., Kawasaki H. and Fujiwara H.
  • Journal Title: Reproductive Biology and Endocrinology Volume: 16 Issue: 1 Pages: 72-72
  • DOI: 10.1186/s12958-018-0381-7
  • Peer Reviewed / Open Access
• [Journal Article] The chemorepellent draxin is involved in hippocampal mossy fiber projection. (2018)
  • Author(s): Tawarayama H, Yamada H, Shinmyo Y, Tanaka H, Ikawa S.
  • Journal Title: Biochem Biophys Res Commun. Volume: 500 Issue: 2 Pages: 217-223
  • DOI: 10.1016/j.bbrc.2018.04.043
  • Peer Reviewed / Open Access
• [Journal Article] Expression of Draxin in Lung Carcinomas (2018)
  • Author(s): Sato Y, Matsuo A, Kudoh S, Liu F, Hasegawa K, Shinmyo Y, Ito T
  • Journal Title: ACTA HISTOCHEMICA ET CYTOCHEMICA Volume: 51 Issue: 1 Pages: 53-62
  • DOI: 10.1267/ahc.17035
  • NAID: 130006405032
  • ISSN: 0044-5991, 1347-5800
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distribution and morphological features of microglia in the developing cerebral cortex of gyrencephalic mammals (2018)
  • Author(s): Mizuguchi K., Horiike T., Matsumoto N., Ichikawa Y., Shinmyo Y. and Kawasaki H.
  • Journal Title: Neurochemical Research Volume: 43 Issue: 5 Pages: 1075-1085
  • DOI: 10.1007/s11064-018-2520-0
  • Description: 掲載確定 印刷中
  • Peer Reviewed
• [Presentation] Folding of the cerebral cortex requires Cdk5 in upper-layer neurons in gyrencephalic mammals (2018)
  • Author(s): Y. Shinmyo, Y. Terashita, T.A. Dinh Duong, T. Horiike, M. Kawasumi, K. Hosomichi, A. Tajima, H. Kawasaki.
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society
• [Presentation] Folding of the cerebral cortex requires Cdk5 in upper-layer neurons in gyrencephalic mammals (2018)
  • Author(s): Y. Shinmyo, Y. Terashita, T.A. Dinh Duong, T. Horiike, M. Kawasumi, K. Hosomichi, A. Tajima, H. Kawasaki.
  • Organizer: 2nd Biennial Meeting of the International Society for Developmental Neuroscience
  • Int'l Joint Research