Published online before print August 5, 2004, doi: 10.1161/01.RES.0000141136.85194.f0
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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
This article has been cited by other articles:
 |
|
 |
|
  M. D. Combs and K. E. Yutzey Heart Valve Development: Regulatory Networks in Development and Disease Circ. Res., August 28, 2009; 105(5): 408 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Allton, A. K. Jain, H.-M. Herz, W.-W. Tsai, S. Y. Jung, J. Qin, A. Bergmann, R. L. Johnson, and M. C. Barton From the Cover: Trim24 targets endogenous p53 for degradation PNAS, July 14, 2009; 106(28): 11612 - 11616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Barrick, R. B. Roberts, M. Rojas, N. M. Rajamannan, C. B. Suitt, K. D. O'Brien, S. S. Smyth, and D. W. Threadgill Reduced EGFR causes abnormal valvular differentiation leading to calcific aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H65 - H75. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Swift and B. M. Weinstein Arterial-Venous Specification During Development Circ. Res., March 13, 2009; 104(5): 576 - 588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Niessen and A. Karsan Notch Signaling in Cardiac Development Circ. Res., May 23, 2008; 102(10): 1169 - 1181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. A. Gude, G. Emmanuel, W. Wu, C. T. Cottage, K. Fischer, P. Quijada, J. A. Muraski, R. Alvarez, M. Rubio, E. Schaefer, et al. Activation of Notch-Mediated Protective Signaling in the Myocardium Circ. Res., May 9, 2008; 102(9): 1025 - 1035. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jia, I. N. King, S. S. Chopra, H. Wan, T. T. Ni, C. Jiang, X. Guan, S. Wells, D. Srivastava, and T. P. Zhong Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5 PNAS, August 28, 2007; 104(35): 14008 - 14013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Fischer and M. Gessler Delta Notch and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors Nucleic Acids Res., July 14, 2007; 35(14): 4583 - 4596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Niessen and A. Karsan Notch signaling in the developing cardiovascular system Am J Physiol Cell Physiol, July 1, 2007; 293(1): C1 - C11. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Xin, E. M. Small, E. van Rooij, X. Qi, J. A. Richardson, D. Srivastava, O. Nakagawa, and E. N. Olson Essential roles of the bHLH transcription factor Hrt2 in repression of atrial gene expression and maintenance of postnatal cardiac function PNAS, May 8, 2007; 104(19): 7975 - 7980. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Bolos, J. Grego-Bessa, and J. L. de la Pompa Notch Signaling in Development and Cancer Endocr. Rev., May 1, 2007; 28(3): 339 - 363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Fischer, C. Steidl, T. U. Wagner, E. Lang, P. M. Jakob, P. Friedl, K.-P. Knobeloch, and M. Gessler Combined Loss of Hey1 and HeyL Causes Congenital Heart Defects Because of Impaired Epithelial to Mesenchymal Transition Circ. Res., March 30, 2007; 100(6): 856 - 863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Koibuchi and M. T. Chin CHF1/Hey2 Plays a Pivotal Role in Left Ventricular Maturation Through Suppression of Ectopic Atrial Gene Expression Circ. Res., March 30, 2007; 100(6): 850 - 855. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Kokubo, S. Tomita-Miyagawa, Y. Hamada, and Y. Saga Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2 Development, February 15, 2007; 134(4): 747 - 755. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Xiang, Y. Sakata, L. Cui, J. M. Youngblood, H. Nakagami, J. K. Liao, R. Liao, and M. T. Chin Transcription factor CHF1/Hey2 suppresses cardiac hypertrophy through an inhibitory interaction with GATA4 Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1997 - H2006. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Watanabe, H. Kokubo, S. Miyagawa-Tomita, M. Endo, K. Igarashi, K. i. Aisaki, J. Kanno, and Y. Saga Activation of Notch1 signaling in cardiogenic mesoderm induces abnormal heart morphogenesis in mouse Development, May 1, 2006; 133(9): 1625 - 1634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Milan, A. C. Giokas, F. C. Serluca, R. T. Peterson, and C. A. MacRae Notch1b and neuregulin are required for specification of central cardiac conduction tissue Development, March 15, 2006; 133(6): 1125 - 1132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Fischer, J. Klattig, B. Kneitz, H. Diez, M. Maier, B. Holtmann, C. Englert, and M. Gessler Hey Basic Helix-Loop-Helix Transcription Factors Are Repressors of GATA4 and GATA6 and Restrict Expression of the GATA Target Gene ANF in Fetal Hearts Mol. Cell. Biol., October 15, 2005; 25(20): 8960 - 8970. [Abstract] [Full Text] [PDF]
|
|