Activation of Wnt/β-catenin signaling in Muller glia protects photoreceptors in a mouse model of inherited retinal degeneration

Patel, Amit K.; Surapaneni, Krishna; Yi, Hyun; Nakamura, Rei; Karli, Sapir; Syeda, Sarah; Lee, Tinthu; Hackam, Abigail S.

doi:10.1016/j.neuropharm.2014.11.015

Cited by 38 publications

(27 citation statements)

References 71 publications

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“…Molecular targets of grape-derived compounds include key pro-survival molecules, such as glycogen synthase kinase 3β (GSK3β) [24] and the transcription factor STAT3 [25], among many others. Interestingly, modulating both GSK3β and STAT3 has been shown to improve photoreceptor survival [26]. Several studies have shown that various dietary supplements, such as supplementation with probiotic bacteria given to mice fed a high-fat diet [27, 28], can significantly regulate cytokines and proinflammatory factors, and the grape diet may follow a similar mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of a grape-supplemented diet in a mouse model of retinal degeneration

et al. 2016

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Objective Retinal degenerations are a class of devastating blinding diseases that are characterized by photoreceptor dysfunction and death. In this study, we tested whether grape consumption, in the form of freeze-dried grape powder (FDGP), improves photoreceptor survival in a mouse model of retinal degeneration. Methods Retinal degeneration was induced in mice by acute oxidative stress using subretinal injection of paraquat and comparisons were to equivalent volumes of injected saline. The grape-supplemented diet was made by formulating base mouse chow with FDGP, corresponding to 3 daily human servings of grapes, and a control diet was formulated with equivalent sugar composition as FDGP (0.68% glucose/0.68% fructose mixture). Mice were placed on the diets at weaning for 5 weeks prior to oxidative stress injury until analysis at 2 weeks post-injection. Retinal function was measured using electroretinography, thickness of the photoreceptor layer was measured using optical coherence tomography, and rows of photoreceptor nuclei were counted on histological sections. Results In mice fed the control diet, oxidative stress significantly reduced photoreceptor layer thickness and photoreceptor numbers. In contrast, retina thickness and photoreceptor numbers were not reduced by oxidative stress in mice on the grape-supplemented diet, indicating significantly higher photoreceptor survival after injury than mice on the control diet. Furthermore, mice on the grape diet showed preservation of retina function after oxidative stress injury compared with mice on the control diet. Conclusions A diet supplemented with grapes rescued retinal structure and function in an oxidative stress-induced mouse model of retinal degeneration, which demonstrates the beneficial effect of grapes on photoreceptors.

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Section: Discussionmentioning

confidence: 99%

Protective effects of a grape-supplemented diet in a mouse model of retinal degeneration

et al. 2016

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“…In contrast, non-canonical Wnt-Ryk signaling at the injury site inhibited spinal cord regeneration (Liu et al, 2008, Miyashita et al, 2009). Furthermore, our group and others demonstrated that Wnt signaling increased survival of RGCs and other retinal neurons after injury (Seitz et al, 2010, Patel et al, 2015b). …”

Section: Introductionmentioning

confidence: 87%

“…The canonical Wnt/β-catenin pathway (referred to as “Wnt” for simplicity) is an essential signaling cascade in the retina and elsewhere in the CNS that regulates retinal development, stem cell proliferation, neuronal regeneration, and neuroprotection from mutation, oxidative stress, laser and light injuries (Kubo et al, 2003, Hunter et al, 2004, Liu et al, 2007, Mizukami et al, 2009, Seitz et al, 2010, Braunger et al, 2013, Liu et al, 2013, Sanges et al, 2013, Patel et al, 2015b). When Wnt ligands bind to the membrane coreceptors LRP5/6 and Frizzled, levels of the central effector β-catenin accumulate in the cytoplasm, allowing β-catenin to translocate into the nucleus where it binds to TCF/LEF transcription factors and induces Wnt target genes (Nusse, 2005).…”

Section: Introductionmentioning

confidence: 99%

Wnt signaling promotes axonal regeneration following optic nerve injury in the mouse

2017

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Adult mammalian CNS axons generally do not regenerate, creating an obstacle to effective repair and recovery after neuronal injury. The canonical Wnt/β-catenin signaling pathway is an essential signal transduction cascade that regulates axon growth and neurite extension in the developing mammalian embryo. In this study, we investigated whether a Wnt/β-catenin signaling activator could be repurposed to induce regeneration in the adult CNS after axonal injury. We used a retinal ganglion cell (RGC) axon crush injury model in a transgenic Wnt reporter mouse, and intravitreal injections were used to deliver Wnt3a or saline to the RGC cell bodies within the retina. Our findings demonstrated that Wnt3a induced Wnt signaling in RGCs and resulted in significant axonal regrowth past the lesion site when measured at two and four weeks post-injury. Furthermore, Wnt3a-injected eyes showed increased survival of RGCs and significantly higher PERG amplitudes compared to the control. Additionally, Wnt3a-induced axonal regeneration and RGC survival was associated with elevated activation of the transcription factor Stat3, and reducing expression of Stat3 using a conditional Stat3 knock-out mouse line led to diminished Wnt3a-dependent axonal regeneration and RGC survival. Therefore, these findings reveal a novel role for retinal Wnt signaling in axonal regrowth and RGC survival following axonal injury, which may lead to the development of novel therapies for axonal regeneration.

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“…Two microliters of PBS, or PQ (Sigma, St. Louis, MO) at increasing doses ranging from 0.2–1 mM were injected. 23, 25 Each mouse was injected in the same area of the eye. The average amount of cellular loss was similar among eyes measured at the same dose of PQ and time point, although the specific pattern of PQ-induced damage was not uniform between each eye.…”

Section: Methodsmentioning

confidence: 99%

“…26 The entire globe was sectioned into 10 µm cross-sections, stained with 4',6-diamidino-2-phenylindole (DAPI) to visualize the retina cell nuclei, and columns of photoreceptor nuclei in the ONL were counted near the optic nerve head and in the periphery in 5 sections, each approximately 200 µm apart. 23, 25 Central photoreceptors were counted approximately 200–300 µm from the optic nerve and peripheral photoreceptors were counted 200–300 µm from the end of the retina/ciliary epithelium.…”

Section: Methodsmentioning

confidence: 99%

Defining the Relationships Among Retinal Function, Layer Thickness and Visual Behavior During Oxidative Stress-Induced Retinal Degeneration

Patel

Akinsoji

Hackam

2015

Current Eye Research

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Purpose The purpose of this study was to identify how changes in retinal structure and function correlate with visual deficits during increasing amounts of retinal degeneration. Materials and Methods Retinal degeneration was induced in adult mice by subretinal injections of paraquat (0.2–1 mM). Retinal anatomy and photoreceptor layer thickness were quantified by histology and optical coherence tomography, retinal function was measured using electroretinography, and visual behavior were measured by optokinetic tracking, at 1–3 weeks post-injury. Results Photoreceptor layer structure, function, and visual behavior declined at a linear rate over time following paraquat induced degeneration, with the correlations between outcome measures being lowest at mild injury levels and increasing with injury severity. Overall reductions in visual acuity were highly correlated with declines in retinal thickness (r2=0.78) and function (r2=0.67) and retinal thickness correlated with photoreceptor function (r2=0.72). ERG a-wave scotopic amplitudes showed a stronger correspondence to in retinal structure and visual behavior than b-waves. Conclusions Measurements of photoreceptor loss at the structural and functional levels showed good correspondence with degeneration-associated changes in visual behavior after oxidative stress injury. The results provide new insight about the relative kinetics of measurements of retinal degeneration induced by oxidative stress, which could guide the choice of optimal outcome measurements for other retinal diseases.

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Activation of Wnt/β-catenin signaling in Muller glia protects photoreceptors in a mouse model of inherited retinal degeneration

Cited by 38 publications

References 71 publications

Protective effects of a grape-supplemented diet in a mouse model of retinal degeneration

Protective effects of a grape-supplemented diet in a mouse model of retinal degeneration

Wnt signaling promotes axonal regeneration following optic nerve injury in the mouse

Defining the Relationships Among Retinal Function, Layer Thickness and Visual Behavior During Oxidative Stress-Induced Retinal Degeneration

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