Dissecting the physiological roles of CNOT4 ubiquitin ligase for prevention of fetal growth restriction.

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K15038
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Akita University
• Principal Investigator: Yamaguchi Tomokazu 秋田大学, 医学系研究科, 助教 (30749940)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: CNOT4 / 胚発生 / ユビキチン転移酵素 / 細胞増殖

Outline of Final Research Achievements

In this study, we analyzed the molecular functions of CNOT4 ubiquitin ligase to dissect its physiological roles in mammalian tissues. Although CNOT4 RING mutant mice show prenatal growth retardation and high postnatal lethality, mutant embryo developed with wild type placenta made by aggregation chimaera also showed developmental deficiency, indicating that occurrence of those phenotypes were independent of placental formation. For further analysis, we generated CNOT4 floxed mice and depleted CNOT4 in MEFs. As a result, significant decrease of cell proliferation rate and increased cell death CNOT4-depleted MEFs were observed. In addition, RNA-seq analysis of CNOT4 knockdown HEK293T cells suggested that CNOT4 positively regulate mRNA expression that contribute to embryonic organ development.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

ユビキチン転移酵素であるCNOT4の哺乳類組織における役割を報告した例はいまだない。本研究では、変異型CNOT4を発現するマウスは胎児期の発育不全と出生後の高い致死率を示すことから、胎児の発育にCNOT4が必須の役割を果たすことがわかり、培養細胞においてはCNOT4が発現しない条件下では発生に必要な種々の遺伝子の発現が有意に低下してしまうことが明らかとなった。以上の発見は、胚発生期におけるユビキチン化修飾と遺伝子発現制御との連携に焦点を当てた新たなパラダイムの構築に繋がり、将来的には胎児発育不全やそれに付随する種々の疾病の解明と新たな治療技法の確立のための重要な基礎情報になると期待している。