Transcriptional Profiling Identifies Upregulation of Neuroprotective Pathways in Retinitis Pigmentosa
| Autor: | Bielmeier, Christina B., Roth, Saskia, Schmitt, Sabrina I., Boneva, Stefaniya K., Schlecht, Anja, Vallon, Mario, Tamm, Ernst R., Ergün, Süleyman, Neueder, Andreas, Braunger, Barbara M. |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Rhodopsin Transcription Genetic QH301-705.5 Mice Transgenic extracellular matrix disorganisation in-situ hybridization Article neuroinflammation Mice GTP-Binding Proteins Retinal Rod Photoreceptor Cells Transforming Growth Factor beta retinitis pigmentosa Glial Fibrillary Acidic Protein Animals Gene Regulatory Networks ddc:610 Biology (General) Extrazelluläre Matrix QD1-999 VPP mouse model Chemokine CCL2 Tiermodell Retinopathia pigmentosa Sequence analysis RNA Gene Expression Profiling Neurodegenerative diseases Retinal Degeneration neurodegeneration Extracellular matrix Neuroinflammatory diseases Neuroprotection Up-Regulation Retinitis pigmentosa Chemistry Models Animal Nervenentzündung Female DDC 610 / Medicine & health Neuroglia neuroprotective pathways Signal Transduction |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 12 International Journal of Molecular Sciences, Vol 22, Iss 6307, p 6307 (2021) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22126307 |
| Popis: | 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 tran- scriptome 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, immunofluores- cence 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 immunos- tained/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 signal- ing. Thus, modulation of these processes and signaling pathways might represent new therapeutic options to delay the degeneration of photoreceptors in diseases like RP. publishedVersion |
| Databáze: | OpenAIRE |
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