Purchase this article with an account.
Enrica Strettoi, Elena Novelli, Ilaria Piano, Claudia M Gargini; Pattern of retinal morphological and functional decay in Tvrm4 rhodopsin mutant mice. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5396.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Genetic variability is a hallmark of Retinitis Pigmentosa (RP), with known mutations in over 60 different genes. Rhodopsin (RHO) mutations prevail and cause 25%- 40% of the dominant cases. Here we describe the phenotype of Tvrm4 mice, which carry a dominant RHO mutation activated upon brief exposure to strong, white light. Tvrm4 mice, devised in the laboratory of Dr. P. Nishina at Jackson's (Budzynski et al., 2010), make it possible to trigger phenotype manifestation outside the period of retinal development, in young adulthood, mimicking the age of onset of typical human RP.
Tvrm4 mice (with a I307N mutation of RHO) aged 2-4 months and wt littermates were given eye drops of atropine, placed in an illuminating box built ad hoc and exposed to pulses (1’, 2’ or 3’) of 12,000 Lux white neon light. After 48 hrs, 7, 14 or 21 days, mice were used for conventional recordings of flash scotopic and photopic ERG. Additional mice were harvested at 48 hrs, 7 and 14 days, their eyes enucleated, fixed and processed for immunocytochemistry and confocal microscopy. Antibodies were used on retinal whole mounts and frozen sections to label rods, cones, bipolar and glial cells.
Exposure of Tvrm4 mice to 12,000 Lux light for either 1', 2' or 3' results in a typical rod-cone degeneration propagating with a center to periphery retinal gradient. Rod outer segments shorten after 48 hrs and their fragments accumulate in the subretinal space. The ONL becomes thinner. Cones degenerate more slowly, first shortening and loosing spatial regularity. Micro and microglial activation and dendritic retraction in the OPL accompany photoreceptor loss. ERG regression is visible at all ages tested, with decrement of scotopic responses preceding that of photopic signals. Upon 2' exposure, after 14 days, scotopic a waves are undetectable, reduced b wave persist and a concomitant decrement of oscillatory potentials is observed. Severity of phenotype increases in time and appears directly related to the duration of bright light exposure.
Unlike other RHO models of RP, Tvrm4 mice are not transgenics; they are inducible, show a typical rod-cone degeneration and a sensitivity to light common to various forms of retinal degeneration. Hence, these mice are an excellent model of RP and can be used to study mechanisms of cell death associated to dominant mutations of RHO as well as to test rescue strategies for human RP.
This PDF is available to Subscribers Only