Loss of αT-catenin alters the hybrid adhering junctions in the heart and leads to dilated cardiomyopathy and ventricular arrhythmia following acute ischemia.

Authors

Jifen Li, Center for Translational Medicine, Department of Medicine, Thomas Jefferson UniversityFollow
Steven Goossens, Department for Molecular Biomedical Research, Flanders Institute for Biotechnology (VIB); Department of Biomedical Molecular Biology, Ghent University
Jolanda van Hengel, Department for Molecular Biomedical Research, Flanders Institute for Biotechnology (VIB); Department of Biomedical Molecular Biology, Ghent University
Erhe Gao, Center for Translational Medicine, Department of Medicine, Thomas Jefferson UniversityFollow
Lan Cheng, Center for Translational Medicine, Department of Medicine, Thomas Jefferson UniversityFollow
Koen Tyberghein, Department for Molecular Biomedical Research, Flanders Institute for Biotechnology (VIB); Department of Biomedical Molecular Biology, Ghent University
Xiying Shang, Center for Translational Medicine, Department of Medicine, Thomas Jefferson UniversityFollow
Riet De Rycke, Department for Molecular Biomedical Research, Flanders Institute for Biotechnology (VIB)
Frans van Roy, Department for Molecular Biomedical Research, Flanders Institute for Biotechnology (VIB); Department of Biomedical Molecular Biology, Ghent University
Glenn L Radice, Center for Translational Medicine, Department of Medicine, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

2-15-2012

Comments

This article has been peer reviewed and is published in Journal of Cell Science.

Volume 125, Issue 4, 15 February 2012, Pages 1058-1067.

The published version is available at DOI: 10.1242/jcs.098640. © The Company of Biologists Ltd.

Abstract

It is generally accepted that the intercalated disc (ICD) required for mechano-electrical coupling in the heart consists of three distinct junctional complexes: adherens junctions, desmosomes and gap junctions. However, recent morphological and molecular data indicate a mixing of adherens junctional and desmosomal components, resulting in a 'hybrid adhering junction' or 'area composita'. The α-catenin family member αT-catenin, part of the N-cadherin-catenin adhesion complex in the heart, is the only α-catenin that interacts with the desmosomal protein plakophilin-2 (PKP2). Thus, it has been postulated that αT-catenin might serve as a molecular integrator of the two adhesion complexes in the area composita. To investigate the role of αT-catenin in the heart, gene targeting technology was used to delete the Ctnna3 gene, encoding αT-catenin, in the mouse. The αT-catenin-null mice are viable and fertile; however, the animals exhibit progressive cardiomyopathy. Adherens junctional and desmosomal proteins were unaffected by loss of αT-catenin, with the exception of the desmosomal protein PKP2. Immunogold labeling at the ICD demonstrated in the αT-catenin-null heart a preferential reduction of PKP2 at the area composita compared with the desmosome. Furthermore, gap junction protein Cx43 was reduced at the ICD, including its colocalization with N-cadherin. Gap junction remodeling in αT-catenin-knockout hearts was associated with an increased incidence of ventricular arrhythmias after acute ischemia. This novel animal model demonstrates for the first time how perturbation in αT-catenin can affect both PKP2 and Cx43 and thereby highlights the importance of understanding the crosstalk between the junctional proteins of the ICD and its implications for arrhythmogenic cardiomyopathy.

Recommended Citation

Li, Jifen; Goossens, Steven; van Hengel, Jolanda; Gao, Erhe; Cheng, Lan; Tyberghein, Koen; Shang, Xiying; De Rycke, Riet; van Roy, Frans; and Radice, Glenn L, "Loss of αT-catenin alters the hybrid adhering junctions in the heart and leads to dilated cardiomyopathy and ventricular arrhythmia following acute ischemia." (2012). Center for Translational Medicine Faculty Papers. Paper 18.
https://jdc.jefferson.edu/transmedfp/18

PubMed ID

22421363