The genetic role of Nodal and Tbx20 in congenital heart and lung defects

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08352
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Keio University
• Principal Investigator: Maeda Jun 慶應義塾大学, 医学部(信濃町), 講師(非常勤) (00255506)
• Co-Investigator(Kenkyū-buntansha): 内田 敬子 慶應義塾大学, 保健管理センター(日吉), 准教授 (50286522)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 先天性心疾患 / NODAL / TBX20

Outline of Final Research Achievements

We previously identified genetic variants of the signaling molecule, NODAL, and the transcription factor, TBX20 in a pedigree with complex heart defects. To delineate the pathogenesis of these variants, we took the genetic approach using genetically engineered mice. Although both heterozygous Nodal knockout mice and heterozygous Tbx20 knockout mice survived after birth and were fertile, the survival rate of double heterozygous knockout mice for Nodal and Tbx20 was significantly decreased at ten days after birth. Most of Tbx20 knockout mice showed ventricular septal defects and decreased the expression level of the transcription factor, Pitx2, which is the downstream target of Nodal in the developmental pathway. Taken together, NODAL and TBX20 may play an essential role in cardiac development in a synergistic fashion and loss of function of both genes may result in more severe heart defects.

Free Research Field

小児循環器学

Academic Significance and Societal Importance of the Research Achievements

私たちは、複雑性先天性心疾患の家族例におけるシグナル分子NODAL、転写因子TBX20の遺伝子異常を同定し、それらを端緒に分子遺伝学的検討を行った。遺伝子操作マウスを用いて、Nodal、Tbx20が心臓発生において共通の分子経路をもち、両者の異常が合併することで先天性心疾患を重症化させる可能性を示した。Tbx20は先天性心疾患の中で最も頻度が高い心室中隔欠損の発症に関与していることが判明し、その分子機構解明により、欠損の発生ならびに自然閉鎖の機序が明らかになる可能性がある。