The results described herein for two mouse models with a “cone-only” retina, namely
Nrl −/− and
Rho −/− mice, point to an essential role of RPE65 in the function of cone photoreceptors, particularly in the supply of the cone visual pigment chromophore. In normal mice (i.e., those expressing NRL and rod opsin and thus having a rod-dominated retina), the absence of RPE65 results in very characteristic changes: (1) 11-
cis retinal is absent,
7 (2) retinyl esters accumulate within the RPE,
7 (3) 9-
cis retinal is the only detectable vitamin A aldehyde,
35 36 and (4) the retinal sensitivity to light is 1000-fold reduced.
8 We observed that the deletion of RPE65 in
Nrl −/− and
Rho −/− mice leads to very similar changes (
Table 1 ,
Fig. 6B ) and therefore conclude that RPE65 is of high functional importance for the retinoid metabolism of both rods and cones. This, however, does not exclude that rods and cones in mice use different pathways for retinoid recycling below the level of RPE65. For example, RPE65 could be the sole entrance for retinoids into the visual cycle of both systems after their absorption from the blood stream and subsequent esterification by lecithin-retinol acyltransferase (LRAT).
2 In this regard, if the cone pathway proposed by Mata et al.
18 for the retina of the chicken and the squirrel would exist in a rod-dominated retina such as that of a mouse, it may be fueled by all-
trans retinol derived from bleached rod visual pigments, and thus indirectly depend on the rod visual cycle and thus RPE65.
37 In the particular situation of the cone-only retinas of
Nrl −/− and
Rho −/− mice, this indirect link via rods would be missing, but RPE65 nevertheless seems to be essential to provide an initial accouterment of 11-
cis retinal for a potential cone-specific visual cycle.