Journal Article

Cardiac-specific deletion of the microtubule-binding protein CENP-F causes dilated cardiomyopathy

Bader, David M., Moynihan, Katherine L., Rottman, Jeffrey N., Dees, Ellen, Hunt, R. Pierre, Galindo, Cristi L., Pooley, Ryan D., Miller, Paul M.

2012

Overview

CENP-F is a large multifunctional protein with demonstrated regulatory roles in cell proliferation, vesicular transport and cell shape through its association with the microtubule (MT) network. Until now, analysis of CENP-F has been limited to in vitro analysis. Here, using a Cre-loxP system, we report the in vivo disruption of CENP-F gene function in murine cardiomyocytes, a cell type displaying high levels of CENP-F expression. Loss of CENP-F function in developing myocytes leads to decreased cell division, blunting of trabeculation and an initially smaller, thin-walled heart. Still, embryos are born at predicted mendelian ratios on an outbred background. After birth, hearts lacking CENP-F display disruption of their intercalated discs and loss of MT integrity particularly at the costamere; these two structures are essential for cell coupling/electrical conduction and force transduction in the heart. Inhibition of myocyte proliferation and cell coupling as well as loss of MT maintenance is consistent with previous reports of generalized CENP-F function in isolated cells. One hundred percent of these animals develop progressive dilated cardiomyopathy with heart block and scarring, and there is a 20% mortality rate. Importantly, although it has long been postulated that the MT cytoskeleton plays a role in the development of heart disease, this study is the first to reveal a direct genetic link between disruption of this network and cardiomyopathy. Finally, this study has broad implications for development and disease because CENP-F loss of function affects a diverse array of cell-type-specific activities in other organs.

• Publisher: The Company of Biologists Ltd,The Company of Biologists Limited,The Company of Biologists
• Subject: Aging - pathology / Animals / Animals, Newborn / Bromodeoxyuridine - metabolism / Cardiomyocytes / Cardiomyopathy / Cardiomyopathy, Dilated - genetics / Cardiomyopathy, Dilated - pathology / Cardiovascular Abnormalities - embryology / Cardiovascular Abnormalities - pathology / Cell cycle / Cell division / Cell Proliferation / Chromosomal Proteins, Non-Histone - deficiency / Chromosomal Proteins, Non-Histone - metabolism / Costameres - metabolism / Disease / Embryos / Fibrosis / Gene Deletion / Gene expression / Gene Expression Profiling / Heart / Heart - embryology / Integrases - metabolism / Mice / Mice, Knockout / Microfilament Proteins - deficiency / Microfilament Proteins - metabolism / Microtubule-associated proteins / Microtubules - metabolism / Morphogenesis / Mutation / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / Organ Specificity / Protein Binding / Protein expression / Proteins / Transcription, Genetic / Troponin T - metabolism