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, 52 (9), 6421-7

Moderate Light-Induced Degeneration of Rod Photoreceptors With Delayed Transducin Translocation in shaker1 Mice

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Moderate Light-Induced Degeneration of Rod Photoreceptors With Delayed Transducin Translocation in shaker1 Mice

You-Wei Peng et al. Invest Ophthalmol Vis Sci.

Abstract

PURPOSE. Usher syndrome is characterized by congenital deafness associated with retinitis pigmentosa (RP). Mutations in the myosin VIIa gene (MYO7A) cause a common and severe subtype of Usher syndrome (USH1B). Shaker1 mice have mutant MYO7A. They are deaf and have vestibular dysfunction but do not develop photoreceptor degeneration. The goal of this study was to investigate abnormalities of photoreceptors in shaker1 mice. METHODS. Immunocytochemistry and hydroethidine-based detection of intracellular superoxide production were used. Photoreceptor cell densities under various conditions of light/dark exposures were evaluated. RESULTS. In shaker1 mice, the rod transducin translocation is delayed because of a shift of its light activation threshold to a higher level. Even moderate light exposure can induce oxidative damage and significant rod degeneration in shaker1 mice. Shaker1 mice reared under a moderate light/dark cycle develop severe retinal degeneration in less than 6 months. CONCLUSIONS. These findings show that, contrary to earlier studies, shaker1 mice possess a robust retinal phenotype that may link to defective rod protein translocation. Importantly, USH1B animal models are likely vulnerable to light-induced photoreceptor damage, even under moderate light.

Figures

Figure 1.
Figure 1.
Shaker1 mice show delayed rod transducin translocation. Immunostaining of transducin α subunit on wild type (A and B) and shaker1 (C and D) retinas after dark adaptation for 6 hours (A and C) and light adaptation (1500 lux) for 1 hour (B and D). Arrows indicate transducin labeling at the rod synaptic terminals. After 1 hour of light exposure, rod synaptic terminals in a wild type mouse (arrows in B) show a very high intensity of transducin labeling, suggesting that a significant amount of transducin has been translocated to the rod synaptic terminals (the yellow labeling in Fig. 1 represents the regions with the highest intensity of transducin immunostaining). Under the same condition, after 1 hour of light exposure, the rod synaptic terminals in a shaker1 mouse (arrows in D) show only very weak labeling of transducin, while the strongest labeling of transducin (yellow color) remains at the rod outer segments, indicating the translocation of rod transducin in shaker1 is delayed. RPE, retinal pigment epithelium; PRL, photoreceptor layer; ONL, outer nuclear layer; OPL, outer plexiform layer; OS, outer segments; IS, inner segments. Arrowheads indicate labeled blood vessels. Scale bar: 25 μm.
Figure 2.
Figure 2.
Activation threshold for rod transducin translocation in shaker1 has been shift to 700 lux. Immunostaining of rod transducin on wild type (A, C, and E) and shaker1 (B, D, and F) retinas after light adaptation for 10 minutes of 200 (A and B), 500 (C and D), and 700 lux (E and F), respectively. Large arrows indicate labeling of transducin in rod inner segments. Small arrows indicate labeling of transducin in the rod synaptic terminals. Arrowheads indicate labeled blood vessels. Other labels are the same as in Fig. 1.
Figure 3.
Figure 3.
Continuous light exposure induces more rod degeneration in shaker1 mice. A and B, Light micrographs of central retinal sections of a 3-month-old control wild type mouse (A) and a 3-month-old shaker1 mouse (B) after 6 days of continuous 2500-lux light exposure. Labels are the same as in Fig. 1. C, Average densities (N = 8) of photoreceptors in the ONL of central retinal cross-sections of 3-month-old wild type (WT) and 3-month-old shaker1 mice after 6 days of continuous 200- and 2500-lux light exposure (LA). P value for WT2500lux/Shaker2500lux < 0.001.
Figure 4.
Figure 4.
A and B, Light micrographs of central retinal sections of a 9-month-old control wild type mouse (A) and a 9-month-old shaker1 mouse (B) after being reared for 6 months under a 1500-lux light/dark cycle. Labels are the same as in Fig. 1. C, Kinetics of rod loss as a function of age in wild type and shaker1 mouse retinas reared under regular vivarium room light (<200 lux at the cage level, yellow line for WT, and black line for shaker1) compared with that reared under a 1500-lux light/dark cycle (blue line for WTL, and red line for shaker1L). Data points represent quantitative measures of rod numbers (average of 4 mice) in the central parts of the retinas. *Statistically significant differences between wild typeL and shaker1 L mice (P < 0.001).
Figure 5.
Figure 5.
Accumulation of superoxide in light adapted shaker1 retinas. Results of DHE experiments on wild type (A) and shaker1 (B) mouse retinas after continuous 2500 lux light adaptation for 6 days. Labels are the same as in Fig. 1. C, Comparing the average number of DHE-positive photoreceptors in four shaker1 and four wild type retinas. *Statistically significant differences between wild type (WT) and shaker1 (Shak) mice (P < 0.001).

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