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

Dees E, Miller PM, Moynihan KL, Pooley RD, Hunt RP, Galindo CL, Rottman JN, Bader DM
Dis Model Mech. 2012 5 (4): 468-80

PMID: 22563055 · PMCID: PMC3380710 · DOI:10.1242/dmm.008680

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.

MeSH Terms (23)

Aging Animals Animals, Newborn Bromodeoxyuridine Cardiomyopathy, Dilated Cardiovascular Abnormalities Cell Proliferation Chromosomal Proteins, Non-Histone Costameres Fibrosis Gene Deletion Gene Expression Profiling Heart Integrases Mice Mice, Knockout Microfilament Proteins Microtubules Myocytes, Cardiac Organ Specificity Protein Binding Transcription, Genetic Troponin T

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