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PEDF Supports Both Photoreceptor and Müller Cell Morphogenesis in Retinal Pigment Epithelium-Deprived Retinas

Monica M. Jablonski

In conditions in which the retinal pigment epithelium (RPE) is dystrophic, carries a genetic mutation, or is physically separated from the neural retina, both photoreceptors and Müller cells undergo degenerative changes that contribute to retinal pathology. PEDF is a glycoprotein with reported neuroprotective and differentiation properties that is secreted in abundance by RPE cells. The “pooling” of PEDF within the interphotoreceptor matrix places this molecule in a prime physical location to affect the neural retina. We have demonstrated in an RPE-deprived, but otherwise intact, eye preparation that PEDF has both neurosupportive and gliosupportive properties. Eyes were dissected from Xenopus laevis tadpoles, and the RPE was removed prior to culturing in medium containing purified PEDF, PEDF plus anti-PEDF, or medium alone. Control eyes matured with an adherent RPE or in medium containing PEDF plus nonimmune serum. Light and electron microscopic analysis was utilized to examine retinal ultrastructure. Photoreceptor-specific and Müller cell-specific proteins were immunolocalized and quantified. RPE removal dramatically altered the cytomorphogenesis and biosynthetic activity of the retina; photoreceptor outer segments were aberrantly assembled, adherens junctions between adjacent photoreceptors and Müller cells failed to form, and opsin and glutamine synthetase expression levels were suppressed concurrent with an upregulation in the expression of glial fibrillary acidic protein (GFAP). Supplementation of the medium with PEDF, however, prevented the degenerative response in both retinal cell types. In particular, outer segment assembly was significantly improved, adherens junctions formed, and opsin and glutamine synthetase levels were supported at near normal levels; however, GFAP expression was suppressed. The morphogenetic effects of PEDF were blocked by the anti-PEDF antibody. These results suggest that PEDF plays a critical role in the final stages of retinal cytomorphogenesis and that PEDF supports both photoreceptors and Müller glia.