Published online before print August 5, 2004, doi: 10.1161/01.RES.0000141136.85194.f0
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Submitted on March 15, 2004
Revised on July 22, 2004
Accepted on July 22, 2004
Targeted Disruption of hesr2 Results in Atrioventricular Valve Anomalies That Lead to Heart Dysfunction
Hiroki Kokubo *;
From the Division of Mammalian Development (H.K., Y.S.), National Institute of Genetics, Mishima, Japan; Graduate School for Advanced Studies (H.K., Y.S.), Mishima, Japan; Pediatric Cardiology (S.M.-T., H.T., Y.N., M.N.), The Heart Institute of Japan, Tokyo Women’s Medical University; Department of Biochemistry and Molecular Biology (R.L.J.), University of Texas, M.D. Anderson Cancer Center, Houston.
* To whom correspondence should be addressed. E-mail: hkokubo{at}lab.nig.ac.jp.
Genes involved in the Notch signaling pathway have been shown to be critical regulators of cardiovascular development. In vitro studies have revealed that the Notch signaling pathway directly regulates transcription of hairy and enhancer of split-related (hesr) genes, encoding basic helix-loop-helix transcription factors. To assess the functional role of hesr genes in cardiovascular development, we generated mice with a targeted disruption of the hesr2 gene and used echocardiography to analyze heart function of the mutant mice. In the early postnatal period, a majority of hesr2 homozygous mice die as a result of congestive heart failure accompanied by pronounced heart enlargement. Transthoracic echocardiography on 5-day-old homozygous mice revealed tricuspid and mitral valve regurgitation and a dilated left ventricular chamber with markedly diminished fractional shortening of the left ventricle. The hemodynamic anomalies were accompanied by morphological changes, such as dysplastic atrioventricular (AV) valves, a perimembranous ventricular septal defect, and a secundum atrial septal defect. AV valve regurgitations attributable to dysplasia of the AV valves were most likely responsible for the heart dysfunction in hesr2 homozygous mice. These observations indicate that the Notch signaling target hesr2 plays an important role in the formation and function of AV valves. In addition, hesr2 activity may be important for proper development of cardiomyocytes, thereby assuring normal left ventricular contractility. Because of the unique spectrum of cardiac anomalies expressed by hesr2-null mice, they represent a useful model system for elucidating the genetic basis of heart dysfunction.
Key words: hesr2, notch signaling pathway • echocardiography • knockout mouse • heart anomaly
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