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      Elk3 Deficiency Causes Transient Impairment in Post-Natal Retinal Vascular Development and Formation of Tortuous Arteries in Adult Murine Retinae

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          Abstract

          Serum Response Factor (SRF) fulfills essential roles in post-natal retinal angiogenesis and adult neovascularization. These functions have been attributed to the recruitment by SRF of the cofactors Myocardin-Related Transcription Factors MRTF-A and -B, but not the Ternary Complex Factors (TCFs) Elk1 and Elk4. The role of the third TCF, Elk3, remained unknown. We generated a new Elk3 knockout mouse line and showed that Elk3 had specific, non-redundant functions in the retinal vasculature. In Elk3(−/−) mice, post-natal retinal angiogenesis was transiently delayed until P8, after which it proceeded normally. Interestingly, tortuous arteries developed in Elk3(−/−) mice from the age of four weeks, and persisted into late adulthood. Tortuous vessels have been observed in human pathologies, e.g. in ROP and FEVR. These human disorders were linked to altered activities of vascular endothelial growth factor (VEGF) in the affected eyes. However, in Elk3(−/−) mice, we did not observe any changes in VEGF or several other potential confounding factors, including mural cell coverage and blood pressure. Instead, concurrent with the post-natal transient delay of radial outgrowth and the formation of adult tortuous arteries, Elk3-dependent effects on the expression of Angiopoietin/Tie-signalling components were observed. Moreover, in vitro microvessel sprouting and microtube formation from P10 and adult aortic ring explants were reduced. Collectively, these results indicate that Elk3 has distinct roles in maintaining retinal artery integrity. The Elk3 knockout mouse is presented as a new animal model to study retinal artery tortuousity in mice and human patients.

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          Most cited references32

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          Actin' together: serum response factor, its cofactors and the link to signal transduction.

          The vast diversity of cellular types and behaviours is mainly the result of combinatorial interactions between a limited number of transcription factors and cellular signalling pathways whose activity is stringently controlled by developmental, cellular and extracellular cues. Studies of serum response factor (SRF) have provided a paradigm for such interactions for some years. Recent advances have shown that two families of SRF cofactors, the ternary complex factors (TCFs) and the myocardin-related transcription factors (MTRFs), are regulated by separate signalling pathways and thereby control SRF target genes differentially. The actin cytoskeleton is both an upstream regulator of MRTF activity, with monomeric actin directly acting as a signal transducer, and a downstream effector, because of the many cytoskeletal target genes. Here we discuss how the competition among cofactors might integrate these distinct signalling pathways into a specific transcriptional response and biological function.
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            Potentiation of serum response factor activity by a family of myocardin-related transcription factors.

            Myocardin is a SAP (SAF-A/B, Acinus, PIAS) domain transcription factor that associates with serum response factor (SRF) to potently enhance SRF-dependent transcription. Here we describe two myocardin-related transcription factors (MRTFs), A and B, that also interact with SRF and stimulate its transcriptional activity. Whereas myocardin is expressed specifically in cardiac and smooth muscle cells, MRTF-A and -B are expressed in numerous embryonic and adult tissues. In SRF-deficient embryonic stem cells, myocardin and MRTFs are unable to activate SRF-dependent reporter genes, confirming their dependence on SRF. Myocardin and MRTFs comprise a previously uncharacterized family of SRF cofactors with the potential to modulate SRF target genes in a wide range of tissues.
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              Isolation and properties of cDNA clones encoding SRF, a transcription factor that binds to the c-fos serum response element.

              The serum response element (SRE) is a sequence required for transient transcriptional activation of genes in response to growth factors. We have isolated cDNA clones encoding serum response factor (SRF), a ubiquitous nuclear protein that binds to the SRE. The SRF gene is highly conserved through evolution, and in cultured cells its transcription is itself transiently increased following serum stimulation. A cDNA clone of SRF expressed in vitro generates protein that forms complexes indistinguishable from those formed with HeLa cell SRF, as judged by DNA binding specificity and the ability to promote SRE-dependent in vitro transcription. SRF binds DNA as a dimer, and the DNA binding/dimerization domain of the protein exhibits striking homology to two yeast regulatory proteins.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                9 September 2014
                : 9
                : 9
                : e107048
                Affiliations
                [1 ]Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany
                [2 ]Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
                [3 ]Centre National de la Recherche Scientifique, Illkirch, France
                [4 ]Institut National de la Santé et de la Recherche Médicale, Illkirch, France
                [5 ]Université de Strasbourg, Illkirch, France
                [6 ]Division of Ocular Neurodegeneration, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
                Medical University Innsbruck, Austria
                Author notes

                Competing Interests: The authors confirm that the corresponding author, Alfred Nordheim, is a PLOS ONE Editorial Board member. This does not alter the authors′ adherence to PLOS ONE Editorial policies and criteria.

                Conceived and designed the experiments: C. Wasylyk C. Weinl MJR BW AN. Performed the experiments: C. Wasylyk C. Weinl MGG SB HR CS MJR VS. Analyzed the data: C. Weinl MGG SB CS MJR MS VS. Contributed reagents/materials/analysis tools: C. Wasylyk MJR MS BW AN. Contributed to the writing of the manuscript: C. Weinl BW AN.

                Article
                PONE-D-14-18490
                10.1371/journal.pone.0107048
                4159304
                25203538
                54e93fb7-1914-446c-a4f8-e8dda780bb5b
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 24 April 2014
                : 6 August 2014
                Page count
                Pages: 14
                Funding
                This work was supported by Hyponet, PLBIO2010 ( http://www.e-cancer.fr, BW); Fondation ARC pour la recherche sur le cancer, SF2010 ( http://www.recherche-cancer.net, BW); Centre national de la recherche scientifique, institutional funds (BW); Université Strasbourg, institutional funds ( http://www.unistra.fr, BW); Deutsche Forschungsgemeinschaft, Se837/6-2 ( http://www.dfg.de, MWS); and German Cancer Aid, 109886 ( http://www.krebshilfe.de, AN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Head
                Eyes
                Ocular System
                Cell Biology
                Signal Transduction
                Genetics
                Genetics of Disease
                Genetic Disorders
                Molecular Genetics
                Molecular Biology
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

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