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

SUMMARY 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.

• Publication year

  2012

• Venue

  Disease Models & Mechanisms

• Publication date

  2012-03-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1242/dmm.008680PMID 22563055PMCID 3380710
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• MicroRNA-1 and -133 Increase Arrhythmogenesis in Heart Failure by Dissociating Phosphatase Activity from RyR2 Complex

  2011cited by this paper
• SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Nav1.5 in Cardiomyocytes

  2011cited by this paper
• Serine-910 phosphorylation of focal adhesion kinase is critical for sarcomere reorganization in cardiomyocyte hypertrophy.

  2011cited by this paper
• Mechanical modulation of cardiac microtubules

  2011cited by this paper
• Nesprin-1 and actin contribute to nuclear and cytoskeletal defects in lamin A/C-deficient cardiomyopathy.

  2011cited by this paper
• Limited forward trafficking of connexin 43 reduces cell-cell coupling in stressed human and mouse myocardium.

  2010cited by this paper
• Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis.

  2010cited by this paper
• The genetics of dilated cardiomyopathy

  2010influential reference
• Ordered Assembly of the Adhesive and Electrochemical Connections within Newly Formed Intercalated Disks in Primary Cultures of Adult Rat Cardiomyocytes

  2010cited by this paper
• SAP 97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Nav 1 . 5 in Cardiomyocytes

  2010cited by this paper
• Murine CENP-F regulates centrosomal microtubule nucleation and interacts with Hook2 at the centrosome.

  2009influential reference
• Kv4 Potassium Channels Form a Tripartite Complex With the Anchoring Protein SAP97 and CaMKII in Cardiac Myocytes

  2009cited by this paper
• Left ventricular global transcriptional profiling in human end-stage dilated cardiomyopathy.

  2009influential reference
• Silencing CENPF in bovine preimplantation embryo induces arrest at 8-cell stage.

  2009cited by this paper
• Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation.

  2009cited by this paper
• Dystrophin is a microtubule-associated protein

  2009cited by this paper
• Dystrophin-glycoprotein complex and vinculin-talin-integrin system in human adult cardiac muscle.

  2009influential reference
• Murine CENPF interacts with syntaxin 4 in the regulation of vesicular transport

  2008influential reference
• CMF1–Rb interaction promotes myogenesis in avian skeletal myoblasts

  2008cited by this paper
• Cardiac developmental defects and eccentric right ventricular hypertrophy in cardiomyocyte focal adhesion kinase (FAK) conditional knockout mice

  2008cited by this paper
• The Genome Browser at UCSC for Locating Genes, and Much More!

  2008cited by this paper
• Loss of mXin α , an intercalated disk protein, results in cardiac hypertrophy and cardiomyopathy with conduction defects

  2008cited by this paper
• Arrhythmogenic right ventricular cardiomyopathy in Boxer dogs is associated with calstabin2 deficiency.

  2008cited by this paper
• Echocardiographic Evaluation of Ventricular Function in Mice

  2007cited by this paper
• Loss of mXinα, an intercalated disk protein, results in cardiac hypertrophy and cardiomyopathy with conduction defects

  2007cited by this paper
• Microtubule plus-end-tracking proteins target gap junctions directly from the cell interior to adherens junctions.

  2007cited by this paper
• Conserved C-terminal domains of mCenp-F (LEK1) regulate subcellular localization and mitotic checkpoint delay.

  2007influential reference
• Signals from both sides: Control of cardiac development by the endocardium and epicardium.

  2007cited by this paper
• Altered expression of a limited number of genes contributes to cardiac decompensation during chronic ventricular tachypacing in dogs.

  2007cited by this paper
• Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy.

  2007cited by this paper
• &agr;-E-Catenin Inactivation Disrupts the Cardiomyocyte Adherens Junction, Resulting in Cardiomyopathy and Susceptibility to Wall Rupture

  2006cited by this paper
• Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interd

  2006cited by this paper
• Cardiac connexins as candidate genes for idiopathic atrial fibrillation

  2006cited by this paper
• Transcriptional Profiles in Liver from Rats Treated with Tumorigenic and Non-tumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil

  2006influential reference
• CENP-F is a novel microtubule-binding protein that is essential for kinetochore attachments and affects the duration of the mitotic checkpoint delay

  2006influential reference
• CytLEK1 is a regulator of plasma membrane recycling through its interaction with SNAP-25.

  2006cited by this paper
• Characterization of Bves expression during mouse development using newly generated immunoreagents

  2006cited by this paper
• Identification of a common gene expression signature in dilated cardiomyopathy across independent microarray studies.

  2006cited by this paper
• α-Myosin Heavy Chain: A Sarcomeric Gene Associated With Dilated and Hypertrophic Phenotypes of Cardiomyopathy

  2005cited by this paper
• Interplay between the retinoblastoma protein and LEK1 specifies stem cells toward the cardiac lineage

  2005cited by this paper
• Influence of cyclical mechanical strain on extracellular matrix gene expression in human lamina cribrosa cells in vitro.

  2005influential reference
• Cytoplasmic LEK1 is a regulator of microtubule function through its interaction with the LIS1 pathway.

  2005influential reference
• Mitosin/CENP-F as a Negative Regulator of Activating Transcription Factor-4*

  2005cited by this paper
• Unstable microtubule capture at kinetochores depleted of the centromere‐associated protein CENP‐F

  2005influential reference
• LEK1 protein expression in normal and dysregulated cardiomyocyte mitosis.

  2005influential reference
• Costameres, focal adhesions, and cardiomyocyte mechanotransduction.

  2005cited by this paper
• Oligonucleotide-microarray analysis of peripheral-blood lymphocytes in severe asthma.

  2005influential reference
• Potassium channels

  2005cited by this paper
• LEK1 Is a Potential Inhibitor of Pocket Protein-mediated Cellular Processes*

  2004influential reference
• The AHNAKs are a class of giant propeller-like proteins that associate with calcium channel proteins of cardiomyocytes and other cells

  2004cited by this paper
• A Fundamental Role for KChIPs in Determining the Molecular Properties and Trafficking of Kv4.2 Potassium Channels*

  2003cited by this paper
• A comparison of normalization methods for high density oligonucleotide array data based on variance and bias

  2003influential reference
• Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis.

  2003cited by this paper
• Mitosin/CENP-F is a conserved kinetochore protein subjected to cytoplasmic dynein-mediated poleward transport

  2003cited by this paper
• Dilated cardiomyopathy: a disease of the intercalated disc?

  2003influential reference
• Metavinculin Mutations Alter Actin Interaction in Dilated Cardiomyopathy

  2002influential reference
• Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy

  2002cited by this paper
• The effects of tubulin-binding agents on stretch-induced ventricular arrhythmias.

  2001cited by this paper
• Cardiomyopathies: from genetics to the prospect of treatment.

  2001influential reference
• Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy.

  2001influential reference
• The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms.

  2001influential reference
• The role of the cytoskeleton in heart failure.

  2000cited by this paper
• Mutations in the Human δ-Sarcoglycan Gene in Familial and Sporadic Dilated Cardiomyopathy, a Disease of the Cytoskeleton and Sarcolemma

  2000cited by this paper
• Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy.

  2000influential reference
• Microtubule Depolymerization Normalizes In Vivo Myocardial Contractile Function in Dogs With Pressure-Overload Left Ventricular Hypertrophy

  2000cited by this paper
• Chronic pressure overload cardiac hypertrophy and failure in guinea pigs: II. Cytoskeletal remodeling.

  1999cited by this paper
• Research article

  1999cited by this paper
• Desmin mutation responsible for idiopathic dilated cardiomyopathy.

  1999cited by this paper
• Restricted expression of cardiac myosin genes reveals regulated aspects of heart tube assembly in zebrafish.

  1999cited by this paper
• The Cloning and Analysis of LEK1 Identifies Variations in the LEK/Centromere Protein F/Mitosin Gene Family*

  1999cited by this paper
• Cytoskeletal role in the transition from compensated to decompensated hypertrophy during adult canine left ventricular pressure overloading.

  1998cited by this paper
• Microtubules are involved in early hypertrophic responses of myocardium during pressure overload.

  1998cited by this paper
• Microtubules modulate cardiomyocyte beta-adrenergic response in cardiac hypertrophy.

  1998cited by this paper
• Actin mutations in dilated cardiomyopathy, a heritable form of heart failure.

  1998cited by this paper
• Microtubules are involved in early hypertrophic responses of myocardium during pressure overload.

  1998cited by this paper
• Cyclin D1 overexpression promotes cardiomyocyte DNA synthesis and multinucleation in transgenic mice.

  1997cited by this paper
• Cytoskeletal mechanics in pressure-overload cardiac hypertrophy.

  1997cited by this paper
• Role of microtubules in myocyte contractile dysfunction during cardiac hypertrophy in the rat.

  1996cited by this paper
• Cardiomyocyte DNA synthesis and binucleation during murine development.

  1996cited by this paper
• The role of the cytoskeleton in left ventricular pressure overload hypertrophy and failure.

  1996cited by this paper
• CENP-F is a protein of the nuclear matrix that assembles onto kinetochores at late G2 and is rapidly degraded after mitosis

  1995cited by this paper
• Characterization of a novel 350-kilodalton nuclear phosphoprotein that is specifically involved in mitotic-phase progression

  1995cited by this paper
• A mutation in the dystrophin gene selectively affecting dystrophin expression in the heart.

  1995cited by this paper
• Expression of the atrial-specific myosin heavy chain AMHC1 and the establishment of anteroposterior polarity in the developing chicken heart.

  1994cited by this paper
• BRIEF REPORT - DELETION OF THE DYSTROPHIN MUSCLE-PROMOTER REGION ASSOCIATED WITH X-LINKED DILATED CARDIOMYOPATHY

  1993cited by this paper
• X‐Linked Dilated Cardiomyopathy Molecular Genetic Evidence of Linkage to the Duchenne Muscular Dystrophy (Dystrophin) Gene at the Xp21 Locus

  1993cited by this paper
• CENP-F is a .ca 400 kDa kinetochore protein that exhibits a cell-cycle dependent localization.

  1993cited by this paper
• Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy.

  1991cited by this paper
• More powerful procedures for multiple significance testing.

  1990influential reference
• The effect of doxorubicin (adriamycin) on cytoplasmic microtubule system in cardiac cells.

  1987cited by this paper
• A vinculin-containing cortical lattice in skeletal muscle: transverse lattice elements ("costameres") mark sites of attachment between myofibrils and sarcolemma.

  1983cited by this paper
• Vinculin is a component of an extensive network of myofibril-sarcolemma attachment regions in cardiac muscle fibers

  1983cited by this paper
• Immunochemical analysis of myosin heavy chain during avian myogenesis in vivo and in vitro

  1982cited by this paper
• Cardiac Conduction Abnormalities in Children with Duchenne's Progressive Muscular Dystrophy: Electrocardiographic Features and Morphologic Correlates

  1982cited by this paper

• Farnesylation-Dependent Kinetochore Targeting of CENP-F Is Essential for Oocyte Meiotic Progression and Female Fertility.

  2025cites this paper
• Pentachloronitrobenzene disturbed murine ventricular wall development by inhibiting cardiomyocyte proliferation via Hec1 downregulation.

  2023cites this paper
• Foxm1 regulates cardiomyocyte proliferation in adult zebrafish after cardiac injury.

  2023cites this paper
• Microtubule plus-end tracking proteins: novel modulators of cardiac sodium channels and arrhythmogenesis

  2023cites this paper
• Foxm1 drives cardiomyocyte proliferation in adult zebrafish after cardiac injury

  2022cites this paper
• The interconnections between the microtubules and mitochondrial networks in cardiocerebrovascular diseases: implications for therapy.

  2022cites this paper
• MAP4 as a New Candidate in Cardiovascular Disease

  2020cites this paper
• Supporting the heart: Functions of the cardiomyocyte's non-sarcomeric cytoskeleton.

  2019cites this paper
• Miro-dependent mitochondrial pool of CENP-F and its farnesylated C-terminal domain are dispensable for normal development in mice

  2018cites this paper
• Disentangling the molecular determinants for Cenp‐F localization to nuclear pores and kinetochores

  2018cites this paper
• Loss of CENP-F Results in Dilated Cardiomyopathy with Severe Disruption of Cardiac Myocyte Architecture

  2018cites this paper
• Regulation of Cenp-F localization to nuclear pores and kinetochores

  2018cites this paper
• Malformations in the Murine Kidney Caused by Loss of CENP‐F Function

  2018cites this paper
• Deep RNA sequencing of pectoralis muscle transcriptomes during late-term embryonic to neonatal development in indigenous Chinese duck breeds

  2017cites this paper
• Identification of transcriptome signature for myocardial reductive stress

  2017cites this paper
• CENP-F , Cancer , and the Heart

  2016cites this paper
• Use of a Novel Panel of Monoclonal Antibodies against CENP-F for the Analysis of Cancerous Cells

  2016cites this paper
• Strømme Syndrome Is a Ciliary Disorder Caused by Mutations in CENPF

  2016cites this paper
• Loss of CENP-F results in distinct microtubule-related defects without chromosomal abnormalities

  2016influential citation
• Mechanobiology of Cardiac Disease and Fibrosis: a Novel Role for Cadherin-11

  2016cites this paper
• Centromere protein F includes two sites that couple efficiently to depolymerizing microtubules

  2015cites this paper
• Implication du cytosquelette dans les dysfonctions myocardiques : exemple de la cardiomyopathie septique

  2013cites this paper