Pleiotropic effects in Eya3knockout mice

Söker, Torben; Dalke, Claudia; Puk, Oliver; Floss, Thomas; Becker, Lore; Bolle, Ines; Favor, Jack; Hans, Wolfgang; Hölter, Sabine M.; Horsch, Marion; Kallnik, Magdalena; Kling, Eva; Moerth, Corinna; Schrewe, Anja; Stigloher, Christian; Topp, Stefanie; Gailus‐Durner, Valérie; Naton, Beatrix; Beckers, Johannes; Fuchs, Helmut; Ivandic, Boris; Klopstock, Thomas; Schulz, Holger; Wolf, Eckhard; Wurst, Wolfgang; Bally‐Cuif, Laure; Angelis, Martin Hrabé de; Graw, Jochen

doi:10.1186/1471-213x-8-118

Cited by 37 publications

(33 citation statements)

References 55 publications

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“…A previous report describing germline deletion of Eya3 noted no defects in eye development or function, although the mutant mice were smaller than the controls. 27 No examination of vascular development in vivo has been previously reported. Although the present study focused on the role of endothelial EYA3, it is expressed in other relevant cells, including smooth muscle cells and retinal microglia.…”

Section: Discussionmentioning

confidence: 99%

“…The Eya3-deficient mouse was reported to have minor functional deficits, including reduced movement and changes in respiratory, heart, and muscle function. 27 We have previously reported a role for the EYA-PTP activity in endothelial and cancer cell motility. 12,28 Because EC migration is a critical component of angiogenesis, the role of Figure 4 EYA tyrosine phosphatase inhibition suppresses neovascularization in retinopathy.…”

Section: Discussionmentioning

confidence: 99%

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The Eyes Absent Proteins in Developmental and Pathological Angiogenesis

Wang

Tadjuidje

Pandey

et al. 2016

The American Journal of Pathology

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Management of neoangiogenesis remains a high-value therapeutic goal. A recently uncovered association between the DNA damage repair pathway and pathological angiogenesis could open previously unexplored possibilities for intervention. An attractive and novel target is the Eyes absent (EYA) tyrosine phosphatase, which plays a critical role in the repair versus apoptosis decision after DNA damage. This study examines the role of EYA in the postnatal development of the retinal vasculature and under conditions of ischemia-reperfusion encountered in proliferative retinopathies. We find that the ability of the EYA proteins to promote endothelial cell (EC) migration contributes to a delay in postnatal development of the retinal vasculature when Eya3 is deleted specifically in ECs. By using genetic and chemical biology tools, we show that EYA contributes to pathological angiogenesis in a model of oxygen-induced retinopathy. Both in vivo and in vitro, loss of EYA tyrosine phosphatase activity leads to defective assembly of g-H2AX foci and thus to DNA damage repair in ECs under oxidative stress. These data reveal the potential utility of EYA tyrosine phosphatase inhibitors as therapeutic agents in inhibiting pathological neovascularization with a range of clinical applications. (Am J Pathol 2016, 186: 568e578; http:// dx

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Eyes Absent Proteins in Developmental and Pathological Angiogenesis

Wang

Tadjuidje

Pandey

et al. 2016

The American Journal of Pathology

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“…Eya1 mutations are associated with isolated cardio-facial syndrome, 12 Eya2 was shown to regulate mTOR, a critical mediator of physiological hypertrophy, 13 and Eya3 mutant mice have been described to have heart problems. 14 …”

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confidence: 99%

“…13,19 Although a role for Eya1 in cardiac physiology and function to date has not been described, Eya2, Eya3, and Eya4 have been specified to affect cardiac function. 7,13,14 It was recently demonstrated that Eya4 regulation of the Na+/K+-ATPase is crucial for the maintenance of cardiac function in zebrafish; 20 a mouse model of Eya4 deficiency additionally revealed abnormal anatomy in the middle ear cavity and the Eustachian tube, leading to otitis media. 21 However, cardiac abnormalities were not reported in this model.…”

mentioning

confidence: 99%

Eya4 Induces Hypertrophy via Regulation of p27 ^kip1

Williams

Hundertmark

Nordbeck

et al. 2015

Circ Cardiovasc Genet

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Background-E193, a heterozygous truncating mutation in the human transcription cofactor Eyes absent 4 (Eya4), causes hearing impairment followed by dilative cardiomyopathy. Methods and Results-In this study, we first show Eya4 and E193 alter the expression of p27 kip1 in vitro, suggesting Eya4 is a negative regulator of p27. Next, we generated transgenic mice with cardiac-specific overexpression of Eya4 or E193. Luciferase and chromatin immunoprecipitation assays confirmed Eya4 and E193 bind and regulate p27 expression in a contradictory manner. Activity and phosphorylation status of the downstream molecules casein kinase-2α and histone deacetylase 2 were significantly elevated in Eya4-but significantly reduced in E193-overexpressing animals compared with wild-type littermates. Magnetic resonance imaging and hemodynamic analysis indicate Eya4-overexpression results in an age-dependent development of hypertrophy already under baseline conditions with no obvious functional effects, whereas E193 animals develop onset of dilative cardiomyopathy as seen in human E193 patients. Both cardiac phenotypes were aggravated on pressure overload. Finally, we identified a new heterozygous truncating Eya4 mutation, E215, which leads to similar clinical features of disease and a stable myocardial expression of the mutant protein as seen with E193. Conclusions-Our

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“…Several other studies also support the role of eya3 as a light-sensing molecule in the retina. For instance, the embryonic zebra fish and mouse retina show eya3 mRNA expression (Soker et al, 2008). Similarly, day-night differences in the eya3 immunoreactivity in the outer nuclear layer support a linkage between the light exposure and eya3 expression in the adult mice retina (Sasaki et al, 2012).…”

Section: Discussionmentioning

confidence: 95%