Endogenous Wnt/?-catenin signaling in Muller cells protects retinal ganglion cells from excitotoxic damage.

ABSTRACT: Purpose:To analyze whether activation of endogenous wingless (Wnt)/?-catenin signaling in Müller cells is involved in protection of retinal ganglion cells (RGCs) following excitotoxic damage. Methods:Transgenic mice with a tamoxifen-dependent ?-catenin deficiency in Müller cells were injected with N-methyl-D-aspartate (NMDA) into the vitreous cavity of one eye to induce excitotoxic damage of the RGCs, while the contralateral eye received PBS only. Retinal damage was quantified by counting the total number of RGC axons in cross sections of optic nerves and measuring the thickness of the retinal layers on meridional sections. Then, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was performed to identify apoptotic cells in retinas of both genotypes. Western blot analyses to assess the level of retinal ?-catenin and real-time RT-PCR to quantify the retinal expression of neuroprotective factors were performed. Results:Following NMDA injection of wild-type mice, a statistically significant increase in retinal ?-catenin protein levels was observed compared to PBS-injected controls, an effect that was blocked in mice with a Müller cell-specific ?-catenin deficiency. Furthermore, in mice with a ?-catenin deficiency in Müller cells, NMDA injection led to a statistically significant decrease in RGC axons as well as a substantial increase in TUNEL-positive cells in the RGC layer compared to the NMDA-treated controls. Moreover, in the retinas of the control mice a NMDA-mediated statistically significant induction of leukemia inhibitory factor (Lif) mRNA was detected, an effect that was substantially reduced in mice with a ?-catenin deficiency in Müller cells. Conclusions:Endogenous Wnt/?-catenin signaling in Müller cells protects RGCs against excitotoxic damage, an effect that is most likely mediated via the induction of neuroprotective factors, such as Lif.

SUBMITTER: Boesl F 

PROVIDER: S-EPMC7058433 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature