| Autor: |
Bielmeier CB; Institute of Anatomy and Cell Biology, Julius-Maximilians-University Wuerzburg, Koellikerstr. 6, D-97070 Würzburg, Germany., Roth S; Institute of Anatomy and Cell Biology, Julius-Maximilians-University Wuerzburg, Koellikerstr. 6, D-97070 Würzburg, Germany., Schmitt SI; Institute of Human Anatomy and Embryology, University of Regensburg, D-93053 Regensburg, Germany., Boneva SK; Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, D-79078 Freiburg, Germany., Schlecht A; Institute of Anatomy and Cell Biology, Julius-Maximilians-University Wuerzburg, Koellikerstr. 6, D-97070 Würzburg, Germany., Vallon M; Institute of Anatomy and Cell Biology, Julius-Maximilians-University Wuerzburg, Koellikerstr. 6, D-97070 Würzburg, Germany., Tamm ER; Institute of Human Anatomy and Embryology, University of Regensburg, D-93053 Regensburg, Germany., Ergün S; Institute of Anatomy and Cell Biology, Julius-Maximilians-University Wuerzburg, Koellikerstr. 6, D-97070 Würzburg, Germany., Neueder A; Department of Neurology, University of Ulm, D-89069 Ulm, Germany., Braunger BM; Institute of Anatomy and Cell Biology, Julius-Maximilians-University Wuerzburg, Koellikerstr. 6, D-97070 Würzburg, Germany. |
| Abstrakt: |
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. |
