Abstract 14891: Traf7 Controls Cardiomyocyte Proliferation In Zebrafish
Genetic programs controlling cardiomyocyte proliferation remain largely unknown. The zebrafish has become a powerful model organism to identify novel disease causing genes and the gene-associated signaling pathways in cardiomyocyte proliferation. In a large-scale ENU-mutagenesis screen for recessive lethal mutations that perturb cardiac function, we recently isolated the zebrafish mutant herzbuckel (hzb). hzb mutant embryos display severely reduced contractility of both heart chambers due to a significantly decreased cardiomyocyte number. By a positional cloning approach we demonstrate that the herzbuckel phenotype is caused by a nonsense-mutation in the zebrafish TNF receptor-associated factor 7 gene (ztraf7), encoding for a novel E3-ubiquitin-ligase. Gene specific knock-down studies reveal a phenocopy of the hzb mutant phenotype whereas injection of wild-type traf7 mRNA in hzb mutant embryos rescues the mutant phenotype indicating that the hzb mutation is indeed responsible for the reduction of cardiomyocytes in hzb mutant embryos. Since TRAF7-NFkB signaling is known to play a role in the regulation of cell proliferation in vitro we screened for abnormabilities in the proliferation behaviour in hzb cardiomyocytes. Interestingly, we find that the reduction in hzb cardiomyocyte quantity is indeed caused by a decreased proliferation rate. Additionally, we show that NFkB activity is downregulated in hzb mutants, suggesting that reduced NFkB activity might be the actual molecular cause of hzb phenotype. These findings demonstrate for the first time an essential role of TRAF7-NFkB signaling in the regulation of cardiomyocyte proliferation in vivo.
- © 2011 by American Heart Association, Inc.