Early Postnatal Cardiac Changes and Premature Death in Transgenic Mice Overexpressing a Mutant Form of Serum Response Factor

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.

Requirement for serum response factor for skeletal muscle growth and maturation revealed by tissue-specific gene deletion in mice

“…The apparent block to myofiber growth after skeletal muscle deletion of Srf is reminiscent of the cardiac phenotype resulting from cardiac expression of dominant negative SRF (39) or cardiac deletion of Srf, which results in embryonic lethality from a defect in ventricular growth and maturation (27,28). Conversely, overexpression of SRF results in lethal cardiomyopathy with associated myocyte hypertrophy in adult cardiac muscle (40).…”

Serum response factor: master regulator of the actin cytoskeleton and contractile apparatus

“…In contrast to the above instances, much in vivo genetic evidence exists for SRF playing a critical role in processes unrelated to cell replication. For example, cardiac-restricted overexpression of either wild-type or dominant-negative SRF results in various forms of heart failure because of severe alterations in contractile gene expression (125,126). Moreover, SRF inactivation or knockdown in D. discoideum (26), Drosophila melanogaster (91), Caenorhabditis elegans (30), and Mus musculus (1,28,55,61,70,78,81,82) does not result in impaired cell proliferation.…”

The expression and role of serum response factor in papillary carcinoma of the thyroid

“…a) SRF is significantly up-regulated in PTC and anaplastic carcinoma as compared to SRF expression in follicular SRF plays a key role in many cellular processes, including cell cycle regulation, apoptosis, cell growth and differentiation and cell-specific gene regulation (3)(4)(5)(6)(7)(8)(9)(10). Accumulating evidence has suggested that SRF plays multiple roles in carcinogenesis and cancer metastasis.…”

“…To date, DNA binding sites for SRFs (serum response elements-SREs) have been found in the promoters of ~50 different genes, including immediateearly genes such as c-fos and Egr-1 (3)(4)(5). Studies have also shown that SRF is involved in various cellular processes such as expression of immediate-early and tissue-specific genes, cell proliferation, differentiation and apoptosis (6)(7)(8)(9)(10). A previous study has demonstrated that SRF plays a role in tumor progression, specifically in the mesenchymal transition of epithelial tumor cells (11).…”