The primary degenerative event in the course of the degeneration is located in the outer nuclear layer of CCDKO mice and leads to the secondary development of RPE damage.
(A) Superior-inferior oriented sagittal semithin histology of the outer retina of CCDKO mice and age-matched C57Bl/6 wildtype mice at the level of the optic disc between 2 weeks and over 20 months of age. A localized drop-out of nuclei from the ONL (white arrowheads) as early as 2 weeks of age in CCDKO mice suggests a primary pathological event in the retina that initiates the progressive inferior retinal degeneration in this model finally leading to the complete loss of retinal layers from 8 months of age onwards. The RPE underneath these lesions is secondarily affected. White arrows: drop out of photoreceptor columns, black arrowheads: descending retinal vessels, INL: inner nuclear layer, OPL: outer plexiform layer, ONL: outer nuclear layer, IS: inner segments, OS: outer segments, RPE: retinal pigment epithelium. (B) Quantitative morphometry of RPE damage on the same sections. We observed an normal age-related increase of RPE damage in wildtype mice (C57Bl/6: Pearson r2 = 0.5562, p<0.0001, N = 37) and observed that the age-related increase of RPE damage in CDDKO mice (CCDKO: Pearson r2 = 0.7115, p<0.0001; N = 43) was significantly higher compared to C57Bl/6 mice (linear regression analysis, p<0.0001),which was significantly more pronounced in CCDKO mice (Pearson r2 = 0.465,p = 0.0007; slope difference: p = 0.01). Nevertheless the RPE damage becomes only significantly higher during late stages of the degeneration suggesting a secondary involvement of the RPE during the degenerative process. Scale bars: 25 µm.