Novel gene expression regulatory system in the brain and its dysregulation in disorder/disease

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07394
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Okinawa Institute of Science and Technology Graduate University
• Principal Investigator: Matsuura Ken 沖縄科学技術大学院大学, 神経回路ユニット, 技術員 (10625742)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: CCR4-NOT

Outline of Final Research Achievements

The CCR4-NOT (CNOT) complex plays a major role in post-transcriptional gene silencing and has two important functions: mRNA degradation and translation inhibition. However, little was known about the role of the CNOT complex in the nervous system. In this study, we conducted omics analyses of gene expression and some behavioral experiments using multiple mouse strains in which the different components of the CNOT complex were deficient in forebrain neurons. These mice exhibited behavioral abnormalities such as hyperactivity and learning disabilities. The omics analyses suggested that the CNOT complex may play a role in protein quality control in neurons. These results are expected to help elucidate the pathogenesis of diseases caused by disruption of gene expression control mechanisms.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

近年、タンパク質翻訳の増大による神経ネットワークの過剰な興奮が自閉症に繋がる事が提唱されており、CNOT3が自閉症リスク遺伝子候補として同定された。更に、CNOT9の新規突然変異を持つ患者は発達・知的障害やてんかんを起こすことが報告されるなど、次々とCNOT変異疾患が明らかになっている。本研究の成果は、これまで分かっていなかったCNOT複合体の脳神経系における役割を、様々なCNOT変異マウスを用いる事により、どのような遺伝子変動があるか、どのような行動異常を呈するかなどを解明しており、脳神経系におけるCNOT複合体の遺伝子発現制御御機構の破綻による障害および疾患の理解に寄与する事が期待される。