Abstract
BackgroundIn the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks.ResultsWe generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired.ConclusionsTogether, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities.
Highlights
In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function
Stage-dependent expression of cytoskeletal proteins in the mouse heart To determine the cardiac functions of mammalian Enabled (Mena) and Vasodilator-stimulated phosphoprotein (VASP) and the associated cytoskeletal proteins, αII-Spectrin and actin, we analyzed the protein levels in wild-type mouse hearts by Western blotting
To determine whether or not the regulation of cytoplasmic actin dynamics at Z- and intercalated discs may be exerted through Mena and VASP, we investigated the sub-cellular distribution of the proteins by confocal microscopy and initially focused on Mena, which is more robustly expressed in the adult heart
Summary
Cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. Mena and VASP increase actin filament assembly by their intrinsic polymerase and anti-capping activities [8] and the latter are impaired by the cyclic nucleotidedependent phosphorylation of the proteins [9,10,11] Because of their ability to modulate distinct modes of actin organization, it has been proposed that Mena and VASP may serve as higher order regulators of the actin cytoskeleton [12]. Given their essential role in regulating actin dynamics, it was surprising that the deletion of the genes encoding Mena or VASP in mice resulted in only mild neuronal or platelet dysfunction [13,14,15,16]. A single allele of Mena is sufficient to rescue the embryonic lethal phenotype [13]
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