Conditional müller cell ablation causes independent neuronal and vascular pathologies in a novel transgenic model

Weiyong Shen*, Marcus Fruttiger, Ling Zhu, Sook H. Chung, Nigel L. Barnett, Joshua K. Kirk, So Ra Lee, Nathan J. Coorey, Murray Killingsworth, Larry S. Sherman, Mark C. Gillies

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

116 Citations (Scopus)

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 neuropro-tective 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.

Original languageEnglish
Pages (from-to)15715-15727
Number of pages13
JournalJournal of Neuroscience
Volume32
Issue number45
DOIs
Publication statusPublished - 7 Nov 2012
Externally publishedYes

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