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Weiyong Shen, Ling Zhu, So-Ra Lee, Sook Chung, Mark Gillies; Modulation of Müller glial-neuronal cell interactions attenuates photoreceptor damage in a novel transgenic model of conditional Müller cell ablation. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5593.
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Neurotrophins can regulate opposing functions for cell survival or apoptosis, depending on which form of the protein is secreted and which receptor and signalling pathway is activated. We have recently developed a novel transgenic model (Rlbp1-CreER-DTA176 transgenic mice) in which conditional and patchy Müller cells ablation leads to rapid photoreceptor apoptosis. This study aimed to evaluate the roles of neurotrophin-3 (NT3) and p75 neurotrophin receptor (P75NTR) in photoreceptor injury in this transgenic model.
Rlbp1-CreER-DTA176 transgenic mice received tamoxifen (TMX) injection for conditional Müller cell ablation at 8-10 weeks of age. Changes in the status of Müller cells, expression of the mature and uncleaved precursor forms of NT3 as well as P75NTR were examined by immunohistochemistry (IHC) and western blot analysis. Furthermore, at 3 and 6 days after TMX induction, the mature form of NT3 and an antibody against P75NTR were injected intravitreally, either alone or in combination, to examine their effects on photoreceptor injury after conditional Müller cell ablation.
TMX induction in Rlbp1-CreER-DTA176 transgenic mice resulted in patchy loss of Müller cells alternating with survival Müller glial activation as revealed by IHC. Western blot showed reduced expression of glutamine synthetase and upregulation of glial fibroblast acidic protein. Patchy loss of Müller cells and reactive Müller cell gliosis were accompanied by reduced expression of the mature form of NT3 and upregulation of pro-NT3 and P75NTR. Intravitreal supplementation of mature NT3 and blockage of P75NTR attenuated photoreceptor damage, with the combination being the most efficient.
Müller glial dysfunction may alter the fine balance of protective and deleterious effects between mature NT3 and pro-NT3, thus contributing to photoreceptor injury. Modulation of the neuroprotective effect of mature neutrophins and the pro-apoptotic mechanism of P75NTR may represent a pharmacological target for neuroprotection in retinal degenerations.
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