Molecular pathogenesis of brain malformations in de novo postzygotic mutations in the brain

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02883
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Itoh Kyoko 京都府立医科大学, 医学(系)研究科(研究院), 特任教授 (80243301)
• Co-Investigator(Kenkyū-buntansha): 藤本 崇宏 京都府立医科大学, 医学(系)研究科(研究院), 講師 (10446114) ; 伏木 信次 京都府立医科大学, 医学(系)研究科(研究院), 特任教授 (80150572)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 脳形成異常 / 体細胞モザイク / 子宮内電気穿孔法

Outline of Final Research Achievements

It is known that somatic activation of PI3K-AKT-MTOR signaling causes malformations of cortical development ranging from hemimegalencephaly to focal cortical dysplasia. In order to elucidate the underlying pathomechanisms, we generated mouse model of somatic mosaicism using in utero electroporation of mutated AKT1E17K in fetal brains. Mutated AKT1-transfected cells showed abnormal migration associated with aberrant expression of cortical layer-specific transcription factors such as Ctip2 and Satb2 and enlarged multipolar cells in the intermediate zone of the fetal cortex. Spatial transcriptomics by Photo Isolation Chemistry revealed that migration disorders might be induced by aberrant reconstruction of actin filaments in the AKT1-mutaed cells. We recapitulated the characteristics of the human brain malformation with mutated AKT1. Further analyses could shed light on the mechanisms involved in disrupted brain development in the somatic mosaicism of the PI3K-AKT-MTOR pathway.

Free Research Field

胎児医学

Academic Significance and Societal Importance of the Research Achievements

体細胞遺伝子バリアントのモザイクで発生する脳形成異常に関して、神経病理学的解析を基盤に置きつつ、分子病態メカニズムの解明を進めた。マウス胎仔脳への子宮内電気穿孔法を用いたバリアント遺伝子導入による分子形態学的解析は、ヒト脳形成異常を再現する有効なin vivoモデルとなった。Photo Isolation Chemistry法を用いた空間トランスクリプトーム解析で、当該モデルにおける遊走異常にアクチン細胞骨格の再構築を制御するシグナル経路が関係している可能性が示された。本研究は、大脳形成異常の分子メカニズムの一端を明らかにし、分子レベルでの治療法を探索する礎となった点で社会的意義が高い。