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C. B. Wright, A. K. Lindsay, M. A. Chrenek, J. H. Boatright, J. M. Nickerson; The Rpe65 Knockout Mouse and the Rd12 Mouse Differ in Phenotype. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3647.
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© ARVO (1962-2015); The Authors (2016-present)
The Rpe65 knockout (KO) mouse and the rd12 mouse, a line with a null mutation in the Rpe65 gene, do not express the Rpe65 protein. Both lines experience retinal degeneration and exhibit similar resultant phenotypic changes with one notable exception: unlike the Rpe65 KO, which lacks fundus abnormalities, some rd12 mice exhibit white dots throughout their retinas. We tested whether these mutant strains were otherwise phenotypically identical by observing their vision-dependent behavior.
The visual acuities of C57Bl/6J, Rpe65 KO, and rd12 mice were determined through optokinetic testing (OKT) using a virtual optomotor system (OptoMotry; CerebralMechanics) that measures vision based on the opto-kinetic response. All mice were maintained according to IACUC protocol and were genotyped through either PCR or allelic discrimination assays. Mice were assessed at postnatal days (P) 30, 45, 60, 75, and 90. Data were analyzed by analysis of variance with post-hoc Student Newman-Keuls testing.
The principal finding is that the visual acuity of the rd12 mice declines much more rapidly, and to a greater extent, than that of Rpe65 KO mice. The visual acuity of wildtype C57Bl/6J mice remained relatively constant at 0.384 +/- 0.021 c/d from P30 to P90. At P30, the visual acuities of Rpe65 KO and rd12 mice were nearly identical, measuring approximately 0.319 +/- 0.002 c/d and 0.304 +/- 0.010 c/d, respectively. Sometime after P45, the acuity of Rpe65 KO mice modestly declined to 0.253 +/- 0.017 c/d, roughly 70% of P30 Rpe65 KO values. This acuity value remained steady through P90. Conversely, before P45 and through to P60, the acuity of rd12 mice dramatically declined by over 60% of P30 rd12 values. A more modest decline of 15% was observed from P60 through P90. Thus, at P90, the visual acuities of wildtype C57Bl/6J, Rpe65 KO, and rd12 mice were 0.378 +/- 0.001, 0.253 +/- 0.017, and 0.049 +/- 0.075 c/d, respectively. The decline in rd12 acuity is statistically significant at P60 through P90, with no diminution in the rate of decline for this period.
Even at the earliest age tested, both Rpe65 KO and rd12 strains had a visual acuity lower than that of wildtype C57Bl/6J mice. This finding is not surprising given the likely role of the Rpe65 gene product in the visual cycle. However, the dramatic phenotypic difference between the two mutants strains as evidenced by their behavior is quite unexpected. We speculate that the rd12 mutation confers negative gain-of-function to Rpe65 and that Rpe65 KO mice and rd12 mice are not identical models for the study of Leber congenital amaurosis, type 2 (LCA2).
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