Abstract
Abstract: :
Purpose: Drosophila lacking the photoreceptor protein phosphatase rdgC undergo a light–specific retinal degeneration. We evaluated whether mice lacking the rdgC homologs, PPEF–2 and PPEF–1, exhibit signs of retinal degeneration and whether these mice are more subject to light–mediated retinal damage. Methods: The PPEF–1 and PPEF–2 genes were individually targeted for deletion in embryonic stem cells. These stem cells were used to generate two lines of mice homozygous for PPEF–1 and PPEF–2 respectively, and subsequently to generate mice lacking both PPEF–1 and PPEF–2 (double knockouts). PPEF–1/PPEF–2 knockout mice were analyzed for retinal degeneration after 1 year of 12 hours on/12 hours off light. Additionally, PPEF–2 knockout mice were exposed to short durations of high–intensity light without pupillary dilation and the retinas were analyzed histologically 48–72 hours later. Results: PPEF–1/PPEF–2 knockout mice did not exhibit evidence of retinal degeneration by ERG analysis and histological staining at 1 year under normal ambient 12 hours on/12 hours off light cycles. Additionally, short durations of high intensity light generated comparable levels of retinal damage when analyzed 48 to 72 hours later. Conclusions: Members of the protein phosphatase with EF hand (PPEF) family (rdgC in Drosophila and PPEF–1 and PPEF–2 in mice) are highly conserved throughout evolution at the protein sequence level and also in their tissue specificity, with rdgC and PPEF–2 both found primarily in photoreceptors. Mutation of these genes, however, results in substantially different phenotypes. While rdgC mutants demonstrate a light dependent retinal degeneration, retinas from PPEF mutants do not appear to have any light sensitivity compared to their wild–type counterparts. These phenotypic differences likely relate to differences in photoreceptor signaling, and to differences in the substrate specificity of these phosphatases in Drosophila and vertebrates.
Keywords: photoreceptors • degenerations/dystrophies