Tolmachova T , Wavre-Shapton ST , Barnard AR , Maclaren RE , Futter CE , Seabra MC
Invest Ophthalmol Vis Sci.2010 May 5 ; ():.
PMID: 20445111[PubMed - as supplied by publisher]
Purpose. Choroideremia (CHM) is a progressive X-linked degeneration of three ocular layers (photoreceptors, retinal pigment epithelium (RPE) and choroid), with a complex and still largely unclear pathogenesis. To investigate the pathophysiology of CHM, we engineered mice with a cell type-specific Chm/Rep1 knock-out (KO).Methods. A mouse line carrying a conditional allele Chm(Flox) was crossed with the transgenic line IRBP-Cre to achieve Chm KO specifically in the photoreceptor layer, and Tyr-Cre to produce Chm KO specifically in the RPE and other pigmented cells. Chm(Flox), Tyr-Cre+ and Chm(Flox), IRBP-Cre+ mice were mated to produce mice with Chm KO in both layers. All mouse lines were studied by histology, electron microscopy, electroretinography (ERG), scanning laser ophthalmoscopy (SLO) and biochemical METHODS: Results. In Chm(Flox), IRBP-Cre+ mice we observed progressive degeneration of photoreceptors in the presence of normal RPE. Chm(Flox), Tyr-Cre+ mice exhibited coat colour dilution and pigment abnormalities of the RPE in the presence of an intact outer nuclear layer. In 6-8 month-old Chm(Flox), Tyr-Cre+, IRBP-Cre+ mice, the degeneration of photoreceptors was accelerated in comparison to Chm(Flox), IRBP-Cre+ mice but levelled with age, such that it was comparable at 12-14 months. Detailed ERG and SLO analysis supported the histopathological findings. Conclusions. Defects in photoreceptors and RPE can arise due to intrinsic defects caused cell-autonomously by the Chm KO. However, when both photoreceptors and RPE are diseased, the dynamics of the degenerative process is altered. Photoreceptor functional deficit and cell death manifest much earlier, suggesting that the diseased RPE accelerates photoreceptor degeneration.
