Pathophysiological analyses of PLEKHG2, a responsible gene for neurodevelopmental disorders, during corticogenesis

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22888
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Institute for Developmental Research Aichi Developmental Disability Center
• Principal Investigator: Nishikawa Masashi 愛知県医療療育総合センター発達障害研究所, 分子病態研究部, リサーチレジデント (00871758)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: 神経発達 / 発達障害 / 細胞骨格 / シグナル伝達 / Gタンパク質

Outline of Final Research Achievements

Homozygosity of the p.Arg204Trp variation in PLEKHG2 (PLEK2) is responsible for microcephaly with intellectual disability. However, the role of PLEK2 during neurodevelopment remains unknown. In this study, we analyzed PLEK2 function during cortical development in vivo. The variant in PLEK2 (PLEK2-RW) showed decreased guanine nucleotide-exchange activity for Rac and Cdc42. Acute knockdown of PLEK2 using in utero electroporation-mediated gene transfer delayed dendritic arbor formation at postnatal day 7 (P7), perhaps because of impaired Rac/Cdc42 and PAK1 signaling pathways. Axon pathfinding was also impaired in PLEK2-deficient neurons. At P14, knockdown of PLEK2 was observed to cause defects in dendritic spine formation. Collectively, these results strongly suggest that PLEK2 has essential roles in the maturation of axon, dendrites, and spines. Moreover, impairment of PLEK2 function is most likely to cause defects in neuronal functions that lead to neurodevelopmental disorders.

Free Research Field

神経発達

Academic Significance and Societal Importance of the Research Achievements

本研究によって、PLEKHG2変異（c.610C > T/p.Arg204Trp）による小頭症・知的障害の病態メカニズムは、PLEKHG2のシグナル不全による神経細胞の分化障害に起因することが強く示唆された。さらに、PLEKHG2のエフェクター分子群（Rac, Cdc42, PAK1）に介入することによって、神経細胞の分化障害を改善することにも成功した。本結果は、PLEKHG2変異による小頭症・知的障害発症機構の解明と、それに対する治療法・薬開発戦略の重要な知見となる。