Abstract
Purpose :
Pigment Epithelium-derived Factor (PEDF) delays the death of photoreceptors in various models of retinal degeneration. We have demonstrated that the absence of Serpinf1, the gene that codes PEDF, increases the susceptibility of retinal cell death in rd10 murine models of inherited retinal degeneration. Transcription factor cone-rod homeobox (CRX) plays a critical role in the regulation of photoreceptor cell differentiation and development. The role of CRX on photoreceptor survival is not known. We aim to investigate the effects of neurotrophic activities on changes in the CRX and its target genes in the mouse retina.
Methods :
Serpinf1-/-, Serpinf1+/-, Serpinf1+/+, rd10 and rd10/Serpinf1-/- mice were used. Retinas were dissected and retinal explants were cultured. Recombinant human PEDF protein and the PEDF derived peptide H105A were used as neurotrophic factors. Zaprinast was used to induce photoreceptor cell death in explant cultures. Mice were treated with H105A peptide eye drops. Levels of transcripts and protein distribution in tissues were determined by qRT-PCR and immunofluorescence, respectively.
Results :
The cellular distribution of CRX protein was altered in photoreceptors of Serpinf1-/- mice as compared to wild type mice. PEDF deficiency decreased CRX in photoreceptors, as shown by immunostaining of Serpinf1-/- and wild type retinal explants. Exogenous PEDF protein treatment promoted survival and increased CRX levels in photoreceptors of both Serpinf1+/+ and Serpinf1-/- retinal explants. While photoreceptor cell death induced by zaprinast was associated with a decrease in CRX protein, PEDF treatment recovered CRX in both Serpin f1+/+ and Serpinf1-/- retinal explant cultures treated with zaprinast. Retinas of rd10 and rd10/Serpinf1-/- mice exhibited lower Crx transcripts levels than those in wild type mice. Exogenous H105A peptide eye drops which is known to promote photoreceptor survival, transiently induced the Crx gene expression in both rd10 and rd10/Serpinf1-/- retinas.
Conclusions :
This study shows an association of the neurotrophic activity of PEDF with CRX upregulation, underscoring the role of the transcription factor CRX in photoreceptor survival.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.