title: Conditional Müllercell ablation causes independent neuronal and vascular pathologies in a novel transgenic model.
abstract: Müller cells are the major glia of the retina that serve numerous functions essential to retinal homeostasis, yet the contribution of Müller glial dysfunction to retinal diseases remains largely unknown. We have developed a transgenic model using a portion of the regulatory region of the retinaldehyde binding protein 1 gene for conditional Müller cell ablation and the consequences of primary Müller cell dysfunction have been studied in adult mice. We found that selective ablation of Müller cells led to photoreceptor apoptosis, vascular telangiectasis, blood-retinal barrier breakdown and, later, intraretinal neovascularization. These changes were accompanied by impaired retinal function and an imbalance between vascular endothelial growth factor-A (VEGF-A) and pigment epithelium-derived factor. Intravitreal injection of ciliary neurotrophic factor inhibited photoreceptor injury but had no effect on the vasculopathy. Conversely, inhibition of VEGF-A activity attenuated vascular leak but did not protect photoreceptors. Our findings show that Müller glial deficiency may be an important upstream cause of retinal neuronal and vascular pathologies in retinal diseases. Combined neuroprotective and anti-angiogenic therapies may be required to treat Müller cell deficiency in retinal diseases and in other parts of the CNS associated with glial dysfunction.
authors.affiliation: Save Sight Institute, The University of Sydney, Sydney 2000, Australia. weiyong.shen@sydney.edu.au
authors.forename: Weiyong
authors.initials: W
authors.lastname: Shen
authors.forename: Marcus
authors.initials: M
authors.lastname: Fruttiger
authors.forename: Ling
authors.initials: L
authors.lastname: Zhu
authors.forename: Sook H
authors.initials: SH
authors.lastname: Chung
authors.forename: Nigel L
authors.initials: NL
authors.lastname: Barnett
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Kirk
authors.forename: SoRa
authors.initials: S
authors.lastname: Lee
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Coorey
authors.forename: Murray
authors.initials: M
authors.lastname: Killingsworth
authors.forename: Larry S
authors.initials: LS
authors.lastname: Sherman
authors.forename: Mark C
authors.initials: MC
authors.lastname: Gillies
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001813:Blood-Retinal Barrier / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D005136:Eye Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology*; D010786:Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012160:Retina / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D015861:Retinal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D058456:Retinal Telangiectasis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology*; D015843:Serpins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D020934:Ciliary Neurotrophic Factor; D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor