The neuroprotective role of TGF-beta signaling for photoreceptors
Final Report Abstract
In this project we analyzed the neuroprotective role of transforming growth factor (TGF) β signaling for photoreceptor survival with the overall aim to identify TGFβ dependent signaling networks and cell populations that control those mechanisms. In a first study, we showed that TGFβ signaling was dysregulated following genetically-mediated (VPP) photoreceptor degeneration concomitant with a significant upregulation of transforming growth factor receptor 2 (Tgfbr2) in retinal neurons and Müller cells. Consequently, we conditionally deleted Tgfbr2 in these cells (Tgfbr2Δoc) in combination with VPP-induced photoreceptor degeneration, to study whether the observed upregulation of Tgfbr2 might act neuroprotective. Intriguingly, VPP-induced photoreceptor degeneration drastically exacerbated neurodegeneration in double mutant retinae (Tgfbr2ΔOC; VPP) compared to VPP retinae. RNA sequencing analyses revealed predominant transcriptomic changes in double mutant retinae that indicated a dysregulation of cellular homeostasis and upregulation of pathways involved in neurodegeneration. Moreover, gene ontology analyses showed, that Tgfbr2 deficiency mediates a shift in expression of MAPK signaling pathway regulators from pro-survival to proapoptosis. In further studies, we investigated whether the observed neuroprotective effect might be mediated directly (photoreceptors) or indirectly (e.g. Müller cells). Thus, we analyzed mouse strains with a cell type specific deletion of Tgfbr2 in photoreceptors or Müller cells. We detected by trend more degenerating cells following light-induced photoreceptor degeneration in both Tgfbr2-deficient models. We also observed here that the total number of degenerating cells in the two Tgfbr2-deficient retinae corresponded to the number of degenerating cells in Tgfbr2Δoc retinae. This observation might suggest that TGFβ signaling acts additive neuroprotective through both mechanisms: directly on photoreceptors and indirectly, e.g. involving Müller cells. In contrast to our initial hypothesis that TGFβ signaling regulates expression of neuroprotective factors such as vascular endothelial growth factor (VEGF), once the animals were crossed into the genetic backgrounds required for the planned experiments, the initially observed downregulation of Vegfa did not reach significance. However, as we observed a significant upregulation of Vegf receptor 2 (Vegfr2) in retinae with VPP- and light-induced degeneration, we still followed the hypothesis that VEGF signaling acts neuroprotective for photoreceptor survival. We therefore studied a mouse model with an inducible deletion of Vegfr2 in the entire eye (Vegfr2Δeye). And indeed, light-exposed Vegfr2Δeye retinae demonstrated significantly more degenerating cells, an effect that resulted in a significantly thinner outer nuclear layer 14 days after light exposure compared to light-exposed controls. We furthermore showed that this effect involved a missing activation (phosphorylation) of the neuroprotective factor Protein kinase B (PKB, or Akt), concomitant with upregulation of pro-apoptotic factors such as Bcl2 associated death promotor (Bad). We conclude that stimulation of TGFβ/VEGF signaling or activation of pro-survival MAPK signaling pathways in retinal neurons and Müller cells might be promising approaches to attenuate the degeneration of photoreceptors in diseases such as retinitis pigmentosa or agerelated macular degeneration.
Publications
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Light Intensity-Dependent Dysregulation of Retinal Reference Genes. Adv Exp Med Biol. 2019;1185:295-299
Bielmeier, Christina B.; Schmitt, Sabrina I. & Braunger, Barbara M.
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New Insights into Endothelin Signaling and Its Diverse Roles in the Retina. Adv Exp Med Biol. 2019;1185:519-523
Schmitt, Sabrina I.; Bielmeier, Christina B. & Braunger, Barbara M.
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TGFβ-Neurotrophin Interactions in Heart, Retina, and Brain. Biomolecules. 2021 Sep 14;11(9):1360
Schlecht, Anja; Vallon, Mario; Wagner, Nicole; Ergün, Süleyman & Braunger, Barbara M.
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Transcriptional Profiling Identifies Upregulation of Neuroprotective Pathways in Retinitis Pigmentosa. Int J Mol Sci. 2021 Jun 11;22(12):6307
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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Deficiency in Retinal TGFβ Signaling Aggravates Neurodegeneration by Modulating Pro-Apoptotic and MAP Kinase Pathways. Int J Mol Sci. 2022 Feb 27;23(5):2626
Bielmeier, Christina B.; Schmitt, Sabrina I.; Kleefeldt, Nikolai; Boneva, Stefaniya K.; Schlecht, Anja; Vallon, Mario; Tamm, Ernst R.; Hillenkamp, Jost; Ergün, Süleyman; Neueder, Andreas & Braunger, Barbara M.
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The Protective Effects of Neurotrophins and MicroRNA in Diabetic Retinopathy, Nephropathy and Heart Failure via Regulating Endothelial Function. Biomolecules. 2022 Aug 12;12(8):1113
Shityakov, Sergey; Nagai, Michiaki; Ergün, Süleyman; Braunger, Barbara M. & Förster, Carola Y.
