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1From the Department of Ophthalmology, Beckman Vision Center, and the 2Department of Anatomy, University of California, San Francisco, California; the 3Department of Genetics, Stanford University School of Medicine, Stanford, California; the 4Departments of Pharmacology, 6Medicine, and 7Microbiology and Immunology, the 5Lineberger Comprehensive Cancer Center, the 8University of North Carolina Neuroscience Center and the 9Program for Molecular Biology and Biotechnology, University of North Carolina, Chapel Hill, North Carolina.
PURPOSE. To determine whether mice that are homozygous for a targeted disruption of the Mer receptor tyrosine kinase gene (merkd) manifest a retinal dystrophy phenotype similar to RCS rats, which carry a mutation in the orthologous gene Mertk.
METHODS. Eyes of merkd and C57BL/6 wild-type (WT) mice were examined by light and electron microscopy, whole-eye rhodopsin measurement, and Ganzfeld electroretinography (ERG).
RESULTS. The merkd mice showed rapid, progressive degeneration of the photoreceptors (PRs). Features of the phenotype common to merkd mice and RCS rats included the absence or near absence of phagosomes in the retinal pigment epithelium (RPE) at the peak of outer segment (OS) disc shedding, accumulation of debris and whorls of membranes at the RPE-OS interface, transient supernormal rhodopsin content and OS lengths, the presence of OS vacuoles beginning at early ages, and a relatively slow removal of pyknotic PR nuclei. Most PRs were missing, and OS debris was removed by approximately postnatal day (P)45. Scotopic ERG responses were lower than age-matched WT responses and declined with PR loss. Photopic responses were preserved better than scotopic responses, corresponding with preferential cone preservation as judged histologically. ERG amplitudes were usually unmeasurable beyond P40, although a small-amplitude scotopic threshold response (STR) could still be elicited at P253 in some mice when only scattered PR nuclei remained.
CONCLUSIONS. Ablation of Mer function in merkd mice results in a retinal phenotype almost identical with that of RCS rats. The similarity in phenotypes between the two rodent models suggests that an RPE phagocytic defect is a feature of all types of retinal degeneration caused by loss of function of Mer tyrosine kinase, perhaps including mutations in human MERTK.
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