Developmental mechanisms of the cerebral cortex in ferrets

2020 Fiscal Year Final Research Report

• 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
• Keywords: 大脳皮質 / フェレット / 脳回 / Cdk5

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.

Free Research Field

神経発生生物学

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。