title: Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae.
abstract: Retinal vessel homeostasis ensures normal ocular functions. Consequently, retinal hypovascularization and neovascularization, causing a lack and an excess of vessels, respectively, are hallmarks of human retinal pathology. We provide evidence that EC-specific genetic ablation of either the transcription factor SRF or its cofactors MRTF-A and MRTF-B, but not the SRF cofactors ELK1 or ELK4, cause retinal hypovascularization in the postnatal mouse eye. Inducible, EC-specific deficiency of SRF or MRTF-A/MRTF-B during postnatal angiogenesis impaired endothelial tip cell filopodia protrusion, resulting in incomplete formation of the retinal primary vascular plexus, absence of the deep plexi, and persistence of hyaloid vessels. All of these features are typical of human hypovascularization-related vitreoretinopathies, such as familial exudative vitreoretinopathies including Norrie disease. In contrast, conditional EC deletion of Srf in adult murine vessels elicited intraretinal neovascularization that was reminiscent of the age-related human pathologies retinal angiomatous proliferation and macular telangiectasia. These results indicate that angiogenic homeostasis is ensured by differential stage-specific functions of SRF target gene products in the developing versus the mature retinal vasculature and suggest that the actin-directed MRTF-SRF signaling axis could serve as a therapeutic target in the treatment of human vascular retinal diseases.
authors.affiliation: Department for Molecular Biology, Interfaculty Institute of Cell Biology, University of Tübingen, Tübingen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Weinl
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Riehle
authors.forename: Dongjeong
authors.initials: D
authors.lastname: Park
authors.forename: Christine
authors.initials: C
authors.lastname: Stritt
authors.forename: Susanne
authors.initials: S
authors.lastname: Beck
authors.forename: Gesine
authors.initials: G
authors.lastname: Huber
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wolburg
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.forename: Alfred
authors.initials: A
authors.lastname: Nordheim
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012164:Retinal Diseases / Q000378:metabolism*; D026362:Serum Response Factor / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014652:Vascular Diseases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C511173:Mrtfa protein, mouse; D012333:RNA, Messenger; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C503315:myocardin-related transcription factor B, mouse; C467480:vascular endothelial growth factor A, mouse; D013629:Tamoxifen
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