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Updated: Jul 29, 2026
Transverse Aortic Constriction in Mice
Published on: April 21, 2010
Early postnatal cardiac changes and premature death in transgenic mice overexpressing a mutant form of serum response
1Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, USA.
Abstract:
Serum response factor (SRF) is a key regulator of a number of extracellular signal-regulated genes important for cell growth and differentiation. A form of the SRF gene with a double mutation (dmSRF) was generated. This mutation reduced the binding activity of SRF protein to the serum response element and reduced the capability of SRF to activate the atrial natriuretic factor promoter that contains the serum response element. Cardiac-specific overexpression of dmSRF attenuated the total SRF binding activity and resulted in remarkable morphologic changes in the heart of the transgenic mice. These mice had dilated atrial and ventricular chambers, and their ventricular wall thicknesses were only 1/2 to 1/3 the thickness of that of nontransgenic mice. Also these mice had smaller cardiac myocytes and had less myofibrils in their myocytes relative to nontransgenic mice. Altered gene expression and slight interstitial fibrosis were observed in the myocardium of the transgenic mice. All the transgenic mice died within the first 12 days after birth, because of the early onset of severe, dilated cardiomyopathy. These results indicate that dmSRF overexpression in the heart apparently alters cardiac gene expression and blocks normal postnatal cardiac growth and development.
Insights
Mutated serum response factor (SRF) overexpression in mice hearts caused severe cardiac defects, leading to dilated cardiomyopathy and early death. This highlights SRF
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Developmental Biology
Background:
- Serum response factor (SRF) is a critical transcription factor regulating genes essential for cell growth and differentiation.
- SRF plays a vital role in cardiac development and function.
- Understanding SRF's regulatory mechanisms is key to deciphering cardiac development.
Purpose of the Study:
- To investigate the functional consequences of a mutated SRF (dmSRF) with reduced DNA-binding activity.
- To determine the impact of cardiac-specific dmSRF overexpression on heart development and function in vivo.
- To elucidate the role of SRF in postnatal cardiac growth and gene expression.
Main Methods:
- Generation of transgenic mice overexpressing a double-mutated SRF (dmSRF) specifically in the heart.
- Assessment of SRF binding activity and promoter activation.
- Morphological, histological, and gene expression analyses of transgenic mouse hearts.
- Evaluation of cardiac function and survival rates.
Main Results:
- Cardiac-specific overexpression of dmSRF significantly reduced SRF binding activity in the heart.
- Transgenic mice exhibited dilated atrial and ventricular chambers, reduced ventricular wall thickness, smaller myocytes, and fewer myofibrils.
- Altered cardiac gene expression and interstitial fibrosis were observed, culminating in severe dilated cardiomyopathy and early postnatal death (within 12 days).
Conclusions:
- Overexpression of dmSRF in the heart disrupts normal cardiac gene expression.
- dmSRF impairs postnatal cardiac growth and development, leading to dilated cardiomyopathy and lethality.
- These findings underscore the critical role of SRF's DNA-binding activity in normal cardiac development.
