Primary Cilia Mediate Retinal Development and Photoreceptor Homeostasis. C. Carter1 ,2, A. Drack3, Q. Zhang1, 2, N. Nuangchamnong4, C. Searby1, 2, V. C. Sheffield1, 2, 3 1) Howard Hughes Medical Institute, University of Iowa Carver College of Medicine, Iowa; 2) Department of Pediatrics, Division of Medical Genetics, University of Iowa Carver College of Medicine, Iowa; 3) Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa; 4) Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Iowa Carver College of Medicine, Iowa.
Retinal degenerative diseases such as retinitis pigmentosa (RP) and macular degeneration are the leading cause of incurable blindness in the western world affecting one in 2,000 individuals worldwide. A common finding shared among these diseases is the loss of photoreceptors leading to blindness. However, the lack of therapy for these diseases is due to a poor understanding of the disease mechanisms leading to the loss of photoreceptors. Recent research implicates cilia, tiny hair-like organelles protruding from the cell surface, in the pathophysiology of photoreceptor loss as forms of retinal degeneration show high penetrance in many human ciliopathies including, Bardet-Biedl syndrome (BBS), Meckel-Gruber syndrome and Leber congenital amaurosis. Animal models of retinal degeneration have been investigated for decades in the hope of understanding the cause of photoreceptor cell death, however, the disease mechanisms leading to photoreceptor loss remain unknown. Here we employ several mouse models with primary cilia dysfunction and we discover a novel cause of retinal degeneration. We find that conditional ablation of the cilia genes IFT88 and BBS1 and the growth factor receptor, PDGFR in retinal glia (PDGFR+ and GFAP+ Cre) leads to photoreceptor degeneration and blunted electroretinogram responses indicating impaired visual function. These unique and novel models allowed us to study the contribution of the inner retina to retinal degeneration for the first time. The blunted visual responses occur in the presence of normal rhodopsin localization and normal photoreceptor outer disk ultrastructure. Moreover, PDGFRCKO mice, display impaired B-wave in the presence of a normal A-wave, indicating that the primary cause of visual deficits in these mice is a result of dysfunction within the inner layers of the retina. Importantly, we demonstrate the specificity of our gene knockouts in retinal Muller cells and other retinal glia with no expression observed in photoreceptors. Together these data introduce a novel, parallel and photoreceptor independent mechanism underlying impaired visual function in ciliopathies in addition to the well-characterized retinal degeneration present. These findings introduce a novel role of cilia and retinal glia in maintaining photoreceptor function and disease mechanism for retinal degeneration.
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