Functional analysis of Ripply3 in the migration of thymus from pharyngeal pouch

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K07274
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48010:Anatomy-related
• Research Institution: Kitasato University
• Principal Investigator: Okubo Tadashi 北里大学, 医学部, 准教授 (10450719)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Keywords: 咽頭弓分節 / 胸腺形成 / 心臓形成 / Ripply3 / 内胚葉

Outline of Final Research Achievements

Ripply3 is a gene expressed in the endoderm and ectoderm of the pharyngeal arch during development and is suggested to be involved in pharyngeal arch segmentation and thymus formation. To elucidate the functions of amino acid sequences WRPW and FPVQ, which are evolutionarily conserved in Ripply3, in thymus formation, we analyzed mice with mutations of these sequences. We found that both WRPW and FRVQ mutant mice had dysplastic thymus, but there was a marked difference in the degree of separation and migration of the thymus from pharynx. Furthermore, in the endoderm-specific Ripply3-deficient mice, the frequency of thymus malformation varied greatly depending on the timing of the deletion. These results suggest that the WRPW and FPVQ sequences of Ripply3 are essential for thymus formation and that the timing of Ripply3 expression in the endoderm of the pharyngeal arch is also important for thymus formation.

Free Research Field

発生学

Academic Significance and Societal Importance of the Research Achievements

胸腺や心臓の形成不全を伴うヒトのDiGeorge症候群は、その欠失領域に存在するTbx1が主な原因だが、Ripply3はTbx1に対する転写抑制因子で、その転写抑制活性はRipply3がもつアミノ酸配列FPVQとWRPWに依存することが培養細胞を用いた解析により示唆されていた。本研究では、これらの配列に変異を導入したマウスを解析し、両配列の胸腺形成における重要性が個体レベルで証明された。また咽頭弓内胚葉と外胚葉に発現するRipply3のうち、内胚葉のRipply3は胸腺の咽頭からの分離・移動に必須なことを示した。これらはヒト先天性疾患の病態解明に大きく貢献すると期待される。