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Involvement of NT3 and P75(NTR) in photoreceptor degeneration following selective Müller cell ablation
Weiyong Shen1, Ling Zhu, So-Ra Lee
1Save Sight Institute, the University of Sydney, 8 Macquarie Street, Sydney 2000, Australia. weiyong.shen@sydney.edu.au.
Background:
Neurotrophins can regulate opposing functions that result in cell survival or apoptosis, depending on which form of the protein is secreted and which receptor and signaling pathway is activated. We have recently developed a transgenic model in which inducible and patchy Müller cell ablation leads to photoreceptor degeneration. This study aimed to examine the roles of mature neurotrophin-3 (NT3), pro-NT3 and p75 neurotrophin receptor (P75(NTR)) in photoreceptor degeneration in this model.
Methods:
Transgenic mice received tamoxifen to induce Müller cell ablation. Changes in the status of Müller and microglia cells as well as expression of mature NT3, pro-NT3 and P75(NTR) were examined by immunohistochemistry and Western blot analysis. Recombinant mature NT3 and an antibody neutralizing 75(NTR) were injected intravitreally 3 and 6 days after Müller cell ablation to examine their effects on photoreceptor degeneration and microglial activation.
Results:
We found that patchy loss of Müller cells was associated with activation of surviving Müller cells and microglial cells, concurrently with reduced expression of mature NT3 and upregulation of pro-NT3 and P75(NTR). Intravitreal injection of mature NT3 and a neutralizing antibody to P75NTR, either alone or in combination, attenuated photoreceptor degeneration and the beneficial effect was associated with inhibition of microglial activation.
Conclusions:
Our data suggest that Müller cell ablation alters the balance between the protective and deleterious effects of mature NT3 and pro-NT3. Modulation of the neuroprotective action of mature NT3 and pro-apoptotic pro-NT3/P75(NTR) signaling may represent a novel pharmacological strategy for photoreceptor protection in retinal disease.
Insights
Müller cell ablation in mice alters neurotrophin-3 (NT3) balance, promoting photoreceptor degeneration. Mature NT3 and blocking P75 neurotrophin receptor (P75NTR) protect against this degeneration.
Area of Science:
- Retinal cell biology
- Neuroscience
- Molecular biology
Background:
- Neurotrophins (NTs) exhibit dual roles, mediating cell survival or apoptosis based on their form and receptor interactions.
- A novel transgenic model with inducible Müller cell ablation causes photoreceptor degeneration.
- This study investigates the roles of mature neurotrophin-3 (NT3), pro-NT3, and p75 neurotrophin receptor (P75NTR) in this degeneration model.
Purpose of the Study:
- To elucidate the specific roles of mature NT3, pro-NT3, and P75NTR in photoreceptor degeneration following Müller cell ablation.
- To understand the interplay between Müller cell status, neurotrophin expression, and photoreceptor survival.
Main Methods:
- Müller cell ablation was induced in transgenic mice using tamoxifen.
- Immunohistochemistry and Western blot analysis assessed Müller cell and microglia status, and expression of mature NT3, pro-NT3, and P75NTR.
- Intravitreal injections of mature NT3 or a P75NTR-neutralizing antibody were administered to evaluate their therapeutic potential.
Main Results:
- Müller cell loss correlated with increased pro-NT3 and P75NTR expression, and decreased mature NT3.
- Photoreceptor degeneration and microglial activation were attenuated by intravitreal injections of mature NT3 or P75NTR-neutralizing antibody.
- Combined treatment showed synergistic protective effects on photoreceptor degeneration.
Conclusions:
- Müller cell ablation disrupts the balance between protective mature NT3 and pro-apoptotic pro-NT3/P75NTR signaling.
- Targeting the pro-NT3/P75NTR pathway and enhancing mature NT3 signaling offers a potential therapeutic strategy for retinal diseases.
- Modulating these pathways may preserve photoreceptor function in various retinal conditions.
