Ventricular transcription factor cascade in the formation of atrioventricular valve and septum during embryonic heart development.

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17318
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Jikei University School of Medicine (2020-2021); National Cardiovascular Center Research Institute (2019)
• Principal Investigator: Seya Daiki 東京慈恵会医科大学, 医学部, ポストドクトラルフェロー (30806021)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 先天性心疾患 / 転写調節因子 / 発現制御 / ノックアウトマウス / 形態形成 / 発生・分化

Outline of Final Research Achievements

This study aims to elucidate the significance of Hey2 and the upstream/downstream transcription factor cascade in cardiac morphogenesis and the mechanisms of morphological abnormalities, such as ventricular septal defect, dysplastic tricuspid valve and hypoplastic right ventricle, caused by the Hey2 gene deletion. We generated Hey2 conditional knockout (cKO) mice specific to the myocardium of the right ventricle and ventricular septum using the Mef2c-AHF-Cre mouse strain and demonstrated that Hey2 played an important role in right ventricular development, at least in part, through mitigating the Tbx2-dependent inhibition of Mycn expression. In the analyses of the upstream transcriptional regulation of Hey2 expression, we identified a distal Hey2 enhancer that was activated by Gata and Tbx20 and was essential for Hey2 expression in the ventricular myocardium.

Free Research Field

循環器医科学

Academic Significance and Societal Importance of the Research Achievements

先天性心疾患は新生児の1%に認められる発症頻度の高い疾患であり、胎生期心臓形成の分子基盤を明らかにすることは、その病因究明や、新規治療薬の開発につながる重要な課題である。Hey2 KOマウスで観察される心臓形態異常（心室中隔欠損、三尖弁閉鎖および右心室低形成）は、ヒト先天性心疾患にも認める典型的な構造異常であり、本研究成果は、これらの疾患の病因として右心室心筋での遺伝子発現の調節異常が関与していることを強く示唆するものである。