Conditional Muller Cell Ablation Causes Independent Neuronal and Vascular Pathologies in a Novel Transgenic Model

Muller cells are the major glia of the retina that serve numerous functions essential to retinal homeostasis, yet the contribution of Muller 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 Muller cell ablation and the consequences of primary Muller cell dysfunction have been studied in adult mice. We found that selective ablation of Muller 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 Muller 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 Muller cell deficiency in retinal diseases and in other parts of the CNS associated with glial dysfunction.