Document Detail

Targeted disruption of hesr2 results in atrioventricular valve anomalies that lead to heart dysfunction.
MedLine Citation:
PMID:  15297376     Owner:  NLM     Status:  MEDLINE    
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 the 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.
Hiroki Kokubo; Sachiko Miyagawa-Tomita; Hirofumi Tomimatsu; Yasumi Nakashima; Makoto Nakazawa; Yumiko Saga; Randy L Johnson
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Publication Detail:
Type:  Journal Article     Date:  2004-08-05
Journal Detail:
Title:  Circulation research     Volume:  95     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2004 Sep 
Date Detail:
Created Date:  2004-09-03     Completed Date:  2005-04-01     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  540-7     Citation Subset:  IM    
Division of Mammalian Development, National Institute of Genetics, Mishima, Japan.
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MeSH Terms
Basic Helix-Loop-Helix Transcription Factors
Eye Proteins / genetics,  physiology*
Gene Expression
Gene Targeting
Growth Disorders / etiology
Heart / growth & development
Heart Defects, Congenital / etiology,  pathology
Heart Failure / etiology
Mice, Knockout
Mitral Valve / abnormalities*,  pathology
Mitral Valve Insufficiency / etiology*,  ultrasonography
Myocardium / metabolism
Repressor Proteins
Tricuspid Valve / abnormalities*,  pathology
Tricuspid Valve Insufficiency / etiology*,  ultrasonography
Ventricular Dysfunction, Left / etiology
Reg. No./Substance:
0/Basic Helix-Loop-Helix Transcription Factors; 0/Eye Proteins; 0/Hey2 protein, mouse; 0/Repressor Proteins

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