Disruption of cardiac Ena-VASP protein localization in intercalated disks causes dilated cardiomyopathy

Eigenthaler, Martin; Engelhardt, Stefan; Schinke, Birgitta; Kobsar, Anna; Schmitteckert, Eva; Gambaryan, Stepan; Engelhardt, Catherine M.; Krenn, Veit; Eliava, Marina; Jarchau, Thomas; Walter, Ulrich; Hein, Lutz

doi:10.1152/ajpheart.00362.2003

Cited by 42 publications

(40 citation statements)

References 34 publications

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“…3C). The cardiac changes probably initiated the embryonic lethality, and were reminiscent of cardiac phenotypes observed following the disruption of TGF-b-Smad signaling (Qi et al, 2007) or following the loss of proteins that regulate actin dynamics such as Ena/VASP (Eigenthaler et al, 2003). Interestingly, both TGF-b-Smad signaling (Tang et al, 2003) and Ena/VASP (Bournier et al, 2006) interact with spectrin, although the levels of neither Ena/VASP (supplementary material Fig.…”

Section: Resultsmentioning

confidence: 97%

Cell organization, growth, and neural and cardiac development require αII-spectrin

Stankewich

Cianci

Stabach

et al. 2011

Journal of Cell Science

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SummarySpectrin a2 (aII-spectrin) is a scaffolding protein encoded by the Spna2 gene and constitutively expressed in most tissues. Exon trapping of Spna2 in C57BL/6 mice allowed targeted disruption of aII-spectrin. Heterozygous animals displayed no phenotype by 2 years of age. Homozygous deletion of Spna2 was embryonic lethal at embryonic day 12.5 to 16.5 with retarded intrauterine growth, and craniofacial, neural tube and cardiac anomalies. The loss of aII-spectrin did not alter the levels of aI-or bI-spectrin, or the transcriptional levels of any b-spectrin or any ankyrin, but secondarily reduced by about 80% the steady state protein levels of bII-and bIII-spectrin. Residual bII-and bIII-spectrin and ankyrins B and G were concentrated at the apical membrane of bronchial and renal epithelial cells, without impacting cell morphology. Neuroepithelial cells in the developing brain were more concentrated and more proliferative in the ventricular zone than normal; axon formation was also impaired. Embryonic fibroblasts cultured on fibronectin from E14.5 (Spna2 2/2 ) animals displayed impaired growth and spreading, a spiky morphology, and sparse lamellipodia without cortical actin. These data indicate that the spectrin-ankyrin scaffold is crucial in vertebrates for cell spreading, tissue patterning and organ development, particularly in the developing brain and heart, but is not required for cell viability.

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Section: Resultsmentioning

confidence: 97%

Cell organization, growth, and neural and cardiac development require αII-spectrin

Stankewich

Cianci

Stabach

et al. 2011

Journal of Cell Science

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“…Development 133 (4) in somitogenesis were observed in embryos expressing an EVH1-GFP dominant-negative protein (Eigenthaler et al, 2003;Vasioukhin et al, 2000), providing additional evidence that the phenotype is specific to inhibition of Ena/VASP function (data not shown). FP 4 -mito expression also resulted in disruption of myotomal junctions, as assessed by immunostaining of tenascin, ␤1-integrin and vinculin (data not shown).…”

Section: Research Articlementioning

confidence: 89%

“…To overcome the problem of redundancy, several studies have used dominant-negative proteins to neutralize the function of all Ena/VASP proteins. This work has revealed additional roles for Ena/VASP proteins in formation of cell-cell junctions in epithelial cells (Vasioukhin et al, 2000), regulation of intercalated disc function in cardiac muscle (Eigenthaler et al, 2003) and migration of pyramidal neurons in the cerebral cortex (Goh et al, 2002). Furthermore, dominant-negative proteins have also been employed to examine the mechanism by which Ena/VASP proteins regulate actin dynamics and cell motility in cultured fibroblasts Bear et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Regulation of somitogenesis by Ena/VASP proteins and FAK duringXenopusdevelopment

Kragtorp

Miller

2006

Development

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The metameric organization of the vertebrate body plan is established during somitogenesis as somite pairs sequentially form along the anteroposterior axis. Coordinated regulation of cell shape, motility and adhesion are crucial for directing the morphological segmentation of somites. We show that members of the Ena/VASP family of actin regulatory proteins are required for somitogenesis in Xenopus. Xenopus Ena (Xena) localizes to the cell periphery in the presomitic mesoderm (PSM), and is enriched at intersomitic junctions and at myotendinous junctions in somites and the myotome, where it co-localizes with ␤1-integrin, vinculin and FAK. Inhibition of Ena/VASP function with dominant-negative mutants results in abnormal somite formation that correlates with later defects in intermyotomal junctions. Neutralization of Ena/VASP activity disrupts cell rearrangements during somite rotation and leads to defects in the fibronectin (FN) matrix surrounding somites. Furthermore, inhibition of Ena/VASP function impairs FN matrix assembly, spreading of somitic cells on FN and autophosphorylation of FAK, suggesting a role for Ena/VASP proteins in the modulation of integrin-mediated processes. We also show that inhibition of FAK results in defects in somite formation, blocks FN matrix deposition and alters Xena localization. Together, these results provide evidence that Ena/VASP proteins and FAK are required for somite formation in Xenopus and support the idea that Ena/VASP and FAK function in a common pathway to regulate integrin-dependent migration and adhesion during somitogenesis.

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“…Recently, the EVH-1 structure of Spred proteins has also been enlightened (54). The EVH-1 domain of VASP was shown to act as a dominant negative form when overexpressed in cardiac myocytes (55). Overexpression of a ⌬C-mutant of Spred-1, missing the Sprouty domain but still containing the EVH-1 and the c-Kit binding domains, demonstrated the dominant negative behavior of Spred-EVH1, as well (45).…”

Section: Dwarfism In Spred-2mentioning

confidence: 99%

Gene Disruption of Spred-2 Causes Dwarfism

Bundschu

Knobeloch

Ullrich³

et al. 2005

Journal of Biological Chemistry

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The impact of the fibroblast growth factor receptor 3 (FGFR3)-mediated signaling pathway on bone growth has been demonstrated by various genetic approaches. Overexpression of fibroblast growth factors (FGFs), several gain-of-function mutations in the FGFR3, and constitutive activation of mitogen-activated protein kinase (MAPK) kinase (MEK1) in chondrocytes have been shown to cause dwarfism in mice by activation of the MAPK signaling pathway. To investigate the previously reported inhibitory role of Spred in the FGFR3/MAPK pathway, we generated mice with a trapped Spred-2 gene. Here we show that lack of functional Spred-2 protein in mice caused a dwarf phenotype, similar to achondroplasia, the most common form of human dwarfism. Spred-2 ؊/؊ mice showed reduced growth and body weight, they had a shorter tibia length, and showed narrower growth plates as compared with wild-type mice. We detected promoter activity and protein expression of Spred-2 in chondrocytes, suggesting an important function of Spred-2 in chondrocytes and bone development. Stimulation of chondrocytes with different FGF concentrations showed earlier and augmented ERK phosphorylation in Spred-2 ؊/؊ chondrocytes in comparison to Spred-2 ؉/؉ chondrocytes. Our observations suggest a model in which loss of Spred-2 inhibits bone growth by inhibiting chondrocyte differentiation through up-regulation of the MAPK signaling pathway.Long bone growth is determined mainly by the process of endochondral ossification, a strictly regulated process that requires proliferation and differentiation of chondrocytes. During this process, chondrocytes in the reserve zone that arise from mesenchymal cells first undergo proliferation, they then exit the cell cycle, undergo terminal hypertrophic differentiation, and finally the synthesized cartilage matrix calcifies and is replaced by bone (1). Various signaling molecules have been shown to regulate and coordinate this complex process of endochondral ossification. Fibroblast growth factor (FGF) 1 signaling plays a major role in a variety of developmental processes and recent results have highlighted its function in the regulation of bone morphogenesis (for review, see Ref.2). FGFs are a large family of at least 23 polypeptides that signal through their binding to specific tyrosine kinase receptors (FGFRs), which constitute a four-member gene family (3). FGF receptor 3 (FGFR3) is expressed in proliferating and prehypertrophic chondrocytes in the epiphyseal growth plates (4 -6). Activating mutations in FGFR3 cause different forms of human dwarfism like achondroplasia, hypochondroplasia, and thanatophoric dysplasia (7-10). The most common form of human dwarfism is achondroplasia with a prevalence at birth of about 1/26,000 (11). Expression of activating FGFR3 mutants in mice reproduces the dwarf phenotype of these skeletal diseases (5, 12-17).In contrast, lack of FGFR3 in mice causes skeletal overgrowth, indicating that FGFR3 signaling inhibits endochondral bone growth (18,19). Similarly, transgenic mice overexpressing FGFs...

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Disruption of cardiac Ena-VASP protein localization in intercalated disks causes dilated cardiomyopathy

Cited by 42 publications

References 34 publications

Cell organization, growth, and neural and cardiac development require αII-spectrin

Cell organization, growth, and neural and cardiac development require αII-spectrin

Regulation of somitogenesis by Ena/VASP proteins and FAK duringXenopusdevelopment

Gene Disruption of Spred-2 Causes Dwarfism

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