Rho family GTPases control the development of neonatal dentate neurons

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K08264
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Institute for Developmental Research Aichi Developmental Disability Center
• Principal Investigator: Ito Hidenori 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, 室長 (40311443)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: 知的障害 / 海馬 / 歯状回 / 低分子量Gタンパク質

Outline of Final Research Achievements

We tried to clarify the roles of Rac1, Rac3 and Cdc42 small GTPases in the development of neonatal dentate gyrus. We introduced knockdown vectors against Rac1 into precursors for dentate granule cells at postnatal day 0 using an electroporation-mediated gene transfer method. After 21 days, Rac1-deficient cells were frequently mispositioned between the granule cell layer and hilus. About 60% of these mislocalized cells expressed a dentate granule cell marker, Prox1. Knockdown of Rac3 also resulted in mislocalization of neonatally born dentate granule cells. In addition, knockdown of Cdc42 also caused mislocalization of dentate granule cells, although the effect was moderate compared to Rac1 and Rac3. Despite the ectopic localization, Rac3- or Cdc42-disrupted mispositioned cells expressed Prox1. These results indicate that Rho signaling pathways differentially regulate the proper localization and differentiation of dentate granule cells.

Free Research Field

神経生物学

Academic Significance and Societal Importance of the Research Achievements

知的障害の発症には、様々な脳部位の機能異常が関与していると推測されている。海馬は脳機能の中心を担う領域の一つである。一方、最近数年の間に、知的障害患者においてRac1、Rac3およびCdc42の遺伝子変異が同定されており、病態との関連を明らかにすることが期待されている。これらのことから、本研究は、海馬発生の分子機構の一端を明らかにするという基礎生物学的な意義があるだけでなく、知的障害の病態や治療法開発への端緒となる研究成果であると考えられる。