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RESEARCH PRODUCT

0331 : Pathophysiology of the ubiquitine ligase E3, PDZRN3, in the development of dilated cardiomyopathies

subject

description

Dilated cardiomyopathy is a major cause of heart failure with a poor prognostic. Molecular mechanisms underlying the transition toward the dilated phenotype are still not known. In heart, individual cardiomyocytes connect some with the others via their extremities by junctional platform (Intercalated Discs, ID) crucial for the mechanical coupling and the anisotropic conduction of the electric signal. In this project, we are interested in an Ubiquitine ligase E3 called PDZRN3, which is expressed and regulated in cardiomyocytes during their maturation. We have previously identified PDZRN3 involvement in the the Wnt Planar Cell Polarity (Wnt/PCP) signaling in vascular morphogenesis. In the heart, the ubiquitine proteasome system plays a fundamental role in the regulation of protein quality control in cells whereby it regulates main processes as protein trafficking, cellular signal transduction and protein degradation. We have developed a transgenic model to overexpress PDZRN3 in cardiomyocytes around birth by crossing a pTRE-PDZRN3-V5 mice with αMHCtTA mice (MHC/PDZRN3-V5). As analyzed by echocardiography and histology, 100% of mutant mice developed a dilated cardiomyopathy between 2- 4 weeks of life, with an EF around 40% and a poor survival after 2 months. As analyzed by immunohistochemistry and Western blot, we found a dramatic loss of Cx43 expression at the ID as soon as 15 days after birth together with a robust nuclear expression of Z01. This was associated with an alteration of myocyte survival, impairment in myocyte architecture and a progressive ventricle fibrosis starting after 3 weeks. This study reveals a novel role of the Wnt/PCP/PDZRN3 signaling in the coordination and the polarized organization of Intercalated Discs.