Regulatory mechanism of neuronal migration in 3D brain tissue

2023 Fiscal Year Final Research Report

• Project/Area Number: 20H00483
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 46:Neuroscience and related fields
• Research Institution: Kyoto University
• Principal Investigator: Kengaku Mineko 京都大学, 高等研究院, 教授 (10303801)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 核輸送 / 微小管モーター / アクトミオシン / 核損傷 / ライブイメージング

Outline of Final Research Achievements

This study aimed to elucidate the force generation mechanism that propels nuclear migration in crowded neural tissue in the developing cerebellar cortex. We demonstrated that the mechanosensor PIEZO1 is activated by the increase in plasma membrane tension in crowded tissue, inducing actomyosin contraction in the posterior plasma membrane via the PKC-Ezrin axis. On the other hand, the nucleus-motor adaptor Nesprin2 generates continuous bidirectional movements along the perinuclear microtubules that move forward in migrating neurons. The nucleus frequently undergoes DNA damage by mechanical stress during neuronal migration in the crowded neural tissue. The DNA double strand breaks (DSBs) are rapidly repaired by the non-homologous end-joining (NHEJ) pathway. We generated conditional deletion mutant of Ligase IV and found that the failure in the NHEJ pathway causes the accumulation of unrepaired DSBs into adulthood, leading to progressive motor deficiency in later life.

Free Research Field

神経発生学

Academic Significance and Societal Importance of the Research Achievements

細胞遊走は、形態形成、免疫監視、がん転移など多くの生理・病理過程を司る。脳皮質形成過程のニューロン遊走の破綻は重篤な脳奇形の原因となるほか、自閉スペクトラム症や統合失調症との関連も指摘されている。本研究では、ニューロンが狭い組織空間を潜り抜けるために有効な力を発生する細胞骨格連携機構を明らかにした。また、組織立体空間のメカノストレスに新生ニューロンが応答する細胞分子機構を初めて見出した。本研究成果は脳皮質形成機構および細胞遊走機構の解明に大きく貢献するもので、細胞遊走の破綻を伴う疾患や、ガン細胞浸潤の病理機構を理解する上で重要な足掛りとなると期待される。