The c-myc proto-oncogene regulates cardiac development in transgenic mice.

Abstract

During the maturation of the cardiac myocyte, a transition occurs from hyperplastic to hypertrophic growth. The factors that control this transition in the developing heart are unknown. Proto-oncogenes such as c-myc have been implicated in the regulation of cellular proliferation and differentiation, and in the heart the switch from myocyte proliferation to terminal differentiation is synchronous with a decrease in c-myc mRNA abundance. To determine whether c-myc can influence myocyte proliferation or differentiation, we examined the in vivo effect of increasing c-myc expression during embryogenesis and of preventing the decrease in c-myc mRNA expression that normally occurs during cardiac development. The model system used was a strain of transgenic mice exhibiting constitutive expression of c-myc mRNA in cardiac myocytes throughout development. In these transgenic mice, increased c-myc mRNA expression was found to be associated with both atrial and ventricular enlargement. This increase in cardiac mass was secondary to myocyte hyperplasia, with the transgenic hearts containing more than twice as many myocytes as did nontransgenic hearts. The results suggest that in the transgenic animals there is additional hyperplastic growth during fetal development. However, this additional proliferative growth is not reflected in abnormal myocyte maturation, as assessed by the expression of the cardiac and skeletal isoforms of a-actin. The results of this study indicate that constitutive expression of c-myc mRNA in the heart during development results in enhanced hyperplastic growth and suggest a regulatory role for this proto-oncogene in cardiac myogenesis.Development of the tissue-specific cells of the heart, the cardiac myocytes, has been extensively studied in vivo. Myocytes proliferate throughout fetal and early postnatal development, followed by a transition whereby proliferation ceases and further cardiac growth occurs through an increase in myocyte size rather than number (5, 9). The factors that control myocyte proliferation and the transition from hyperplastic to hypertrophic growth are unknown.Recent interest has centered on the role of proto-oncogenes in cellular development. In particular, c-myc has been implicated in controlling both proliferation and differentiation in various cell types (29). Increased expression of c-myc in chicken embryo fibroblasts results in an increase in the rate of proliferation of these cells (34). In hematopoietic cells, the expression of c-myc decreases concomitant with differentiation, and if these cells are made to constitutively express c-myc, differentiation is prevented (10,13,25,33 genes) encode proteins that induce myogenic determination in skeletal muscle. These genes all share regions of similarity with c-myc, suggesting a potential interaction of these gene products with c-myc, or with a common intracellular target, in regulating skeletal muscle differentiation. Although expression of these particular myogenic determination genes has not been observed in heart (4, 11, 43...

Cardiac hypertrophy in juvenile visceral steatosis (jvs) mice with systemic carnitine deficiency

“…To our knowledge, 3 kinds of animal models for cardiac hypertrophy have been reported: spontaneously hypertensive rat (SHR) [25], syrian hamster with cardiomyopathy [26], and c-myc transgenic mice [27]. Although the mechanism causing cardiac hypertrophy in the former two animals is suspected to be in the abnormality of the cardiac cellular membrane [28,29], this is still not clear.…”

Cardiomyocyte Proliferation: A Platform for Mammalian Cardiac Repair

“…Transgenic overexpression of oncogenes/cell cycle promoters has led to cell cycle activation in adult cardiomyocytes but still failed to prove cell division. 27,[29][30][31][32][33] Recently, a major step forward was made by demonstrating that targeted expression of Cyclin D2 in cardiomyocytes leads to DNA synthesis in vivo and infarct regression. Although this study presents several indirect proofs for cardiomyocyte proliferation (increase in DNA synthesis, mitotic figures, and cell number based on mathematical calculations), the clear evidence that adult cardiomyocytes proliferate is still lacking.…”

“…This might be the reason why most studies trying to induce cardiomyocyte proliferation have focused on inducers of proliferation, namely growth factors, cell cycle genes, and oncogenes. [27][28][29][30][31][32][33] However, these attempts were not successful. Based on the observation that cardiac tumors occur very rarely, this is not a surprising result.…”

Underlying mechanisms and prospects of heart regeneration

“…Jackson et al (1990) overexpressed c-Myc during embryogenesis of mice and demonstrated both increased cardiomyocyte numbers (almost twofold) and heart weight (Jackson et al, 1990). In another study, adenoviral overexpression of oncogene E1A in cardiomyocytes resulted in induced cardiomyocyte cycling followed by apoptosis (Liu and Kitsis, 1996).…”