transforming-growth-factor-beta and Retinitis-Pigmentosa

Hereditary retinal degenerations like retinitis pigmentosa (RP) are among the leading causes of blindness in younger patients. To enable in vivo investigation of cellular and molecular mechanisms responsible for photoreceptor cell death and to allow testing of therapeutic strategies that could prevent retinal degeneration, animal models have been created. In this study, we deeply characterized the transcriptional profile of mice carrying the transgene rhodopsin V20G/P23H/P27L (VPP), which is a model for autosomal dominant RP. We examined the degree of photoreceptor degeneration and studied the impact of the VPP transgene-induced retinal degeneration on the transcriptome level of the retina using next generation RNA sequencing (RNASeq) analyses followed by weighted correlation network analysis (WGCNA). We furthermore identified cellular subpopulations responsible for some of the observed dysregulations using in situ hybridizations, immunofluorescence staining, and 3D reconstruction. Using RNASeq analysis, we identified 9256 dysregulated genes and six significantly associated gene modules in the subsequently performed WGCNA. Gene ontology enrichment showed, among others, dysregulation of genes involved in TGF-β regulated extracellular matrix organization, the (ocular) immune system/response, and cellular homeostasis. Moreover, heatmaps confirmed clustering of significantly dysregulated genes coding for components of the TGF-β, G-protein activated, and VEGF signaling pathway. 3D reconstructions of immunostained/in situ hybridized sections revealed retinal neurons and Müller cells as the major cellular population expressing representative components of these signaling pathways. The predominant effect of VPP-induced photoreceptor degeneration pointed towards induction of neuroinflammation and the upregulation of neuroprotective pathways like TGF-β, G-protein activated, and VEGF signaling. Thus, modulation of these processes and signaling pathways might represent new therapeutic options to delay the degeneration of photoreceptors in diseases like RP.

Topics: Animals; Chemokine CCL2; Female; Gene Expression Profiling; Gene Regulatory Networks; Glial Fibrillary Acidic Protein; GTP-Binding Proteins; Male; Mice; Mice, Transgenic; Neuroglia; Neuroprotection; Retinal Degeneration; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Rhodopsin; Signal Transduction; Transcription, Genetic; Transforming Growth Factor beta; Up-Regulation; Vascular Endothelial Growth Factor A

NGF is implicated in retinal damage regression. To study whether this is a direct effect or an effect mediated by NGF on other endogenous biological mediators, we investigated the effect of exogenous administration of NGF in RCS rats affected by retinitis pigmentosa. We found that NGF administration exerts a rescue effect on photoreceptors in this animal model. NGF injection enhances brain-derived neurotrophic factor, beta-fibroblast growth factor, transforming growth factor-beta, vascular endothelial factor and neuropeptide-Y. This suggests that NGF has an effect on RCS rat retina, probably also through the stimulation of other biological mediators produced and released in the retina.

Topics: Animals; Brain-Derived Neurotrophic Factor; Eye Proteins; Fibroblast Growth Factors; Needles; Nerve Growth Factor; Neuropeptide Y; Photoreceptor Cells; Rats; Rats, Inbred Strains; Receptor, trkA; Retina; Retinal Vessels; Retinitis Pigmentosa; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A