title: Elk3 deficiency causes transient impairment in post-natal retinal vascular development and formation of tortuous arteries in adult murine retinae.
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.
authors.affiliation: Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Weinl
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, Illkirch, France; Université de Strasbourg, Illkirch, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Wasylyk
authors.affiliation: Division of Ocular Neurodegeneration, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Garcia Garrido
authors.affiliation: Division of Ocular Neurodegeneration, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
authors.forename: Vithiyanjali
authors.initials: V
authors.lastname: Sothilingam
authors.affiliation: Division of Ocular Neurodegeneration, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
authors.forename: Susanne C
authors.initials: SC
authors.lastname: Beck
authors.affiliation: Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Riehle
authors.affiliation: Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Stritt
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, Illkirch, France; Université de Strasbourg, Illkirch, France.
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Roux
authors.affiliation: Division of Ocular Neurodegeneration, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, Illkirch, France; Université de Strasbourg, Illkirch, France.
authors.forename: Bohdan
authors.initials: B
authors.lastname: Wasylyk
authors.affiliation: Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Nordheim
mesh_terms: D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007593:Joint Instability / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D050783:Proto-Oncogene Proteins c-ets / Q000172:deficiency* / Q000235:genetics*; D042764:Receptors, TIE / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology*; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology*; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012873:Skin Diseases, Genetic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D054079:Vascular Malformations / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D042682:Angiopoietins; C086924:Elk3 protein, mouse; D050783:Proto-Oncogene Proteins c-ets; D026362:Serum Response Factor; D014157:Transcription Factors; D042442:Vascular Endothelial Growth Factors; D042764:Receptors, TIE