title: Cardiac-specific deletion of the microtubule-binding protein CENP-F causes dilated cardiomyopathy.
abstract: 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.
authors.affiliation: Department of Pediatrics, Vanderbilt University, Nashville, TN 37232-6300, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Dees
authors.forename: Paul M
authors.initials: PM
authors.lastname: Miller
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Moynihan
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Pooley
authors.forename: R Pierre
authors.initials: RP
authors.lastname: Hunt
authors.forename: Cristi L
authors.initials: CL
authors.lastname: Galindo
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Rottman
authors.forename: David M
authors.initials: DM
authors.lastname: Bader
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000473:pathology*; D018376:Cardiovascular Abnormalities / Q000196:embryology / Q000473:pathology; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency* / Q000378:metabolism; D054974:Costameres / Q000378:metabolism; D005355:Fibrosis; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006321:Heart / Q000196:embryology; D019426:Integrases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency* / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D011485:Protein Binding; D014158:Transcription, Genetic; D020107:Troponin T / Q000378:metabolism
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D008840:Microfilament Proteins; D020107:Troponin T; C094772:centromere protein F; C045073:Cre recombinase; D019426:Integrases; D001973:Bromodeoxyuridine