Early postnatal cardiac changes and premature death in transgenic mice overexpressing a mutant form of serum response factor

Serum response factor (SRF) is a key regulator of a number of extracellular signal-regulated genes important for cell growth and differentiation. A fo rm of the SRF gene with a double mutation (dmSRF) was generated. This mutat ion reduced the binding activity of SRF protein to the serum response eleme nt and reduced the capability of SRF to activate the atrial natriuretic fac tor promoter that contains the serum response element. Cardiac-specific ove rexpression of dmSRF attenuated the total SRF binding activity and resulted in remarkable morphologic changes in the heart of the transgenic mice. The se mice had dilated atrial and ventricular chambers, and their ventricular wall thicknesses were only (1)/(2) to (1)/(3) the thickness of that of nont ransgenic mice. Also these mice had smaller cardiac myocytes and had less m yofibrils in their myocytes relative to nontransgenic mice. Altered gene ex pression and slight interstitial fibrosis were observed in the myocardium. of the transgenic mice. All the transgenic mice died within the first 12 da ys after birth, because of the early onset of severe, dilated cardiomyopath y. These results indicate that dmSRF overexpression in the heart apparently alters cardiac gene expression and blocks normal postnatal cardiac growth and development.