The goal of our research program is to identify molecules that are necessary for normal retinal development and function by using mouse models as an entry point for gene identification and for elucidation of gene function and mechanisms underlying disease pathologies. This renewal application focuses on three unique models, retinal degeneration 7 (rd7), retinal degeneration 6 (rd6) and retinal dysplasia 1 (rdp1), which clinically all exhibit retinal spotting and strikingly similar retinal dysplasia that manifest as folds and rosettes of the PR layer early in life. rd6 and rd7 also exhibit progressive late-onset panretinal degeneration. Interestingly, double mutants homozygous for both rd6 and rdp1 show an earlier and more severe retinal dysplasia than mice homozygous for rd6 alone, suggesting an interaction between the two mutations. Clinically these mutants are most reminiscent of flecked retinal disorders in humans. In this proposal, we build our studies upon what we have learned previously. We are currently at different stages in the investigation of each model. For rd7, we know the gene, Nr2e3, a member of the steroid/thyroid hormone receptor superfamily of ligand-activated transcription factors, and here, we propose to further examine its role in cone cell differentiation and the mechanism for the apparent increase in S-opsin immunoreactive cells. We also plan to identify co-regulators and downstream targets of this Nr2e3 to determine the context in which it functions. For rd6, we are in the final stages of positional cloning and are examining candidates. To assist in choosing candidates, we are further defining the rd6 phenotype. We plan to make aggregation chimeras to determine the site of action of the mutant gene and to do autoradiographic studies to determine if the reduction in phagosomes may be affected by alterations in outer segment (OS) renewal or shedding. In the case of rdpl, a gene that appears to interact with rd6 to cause a more severe retinal phenotype and is histologically similar to the rd7 mutant, we are in he initial stages of mapping. We will construct a genetic map of rdp1 with the goal of positionally cloning it. Finally, we will determine the temporal and spatial expression of rd6 and rdp1 by in situ and by immunohistochemistry once the genes are identified. Identification of disease-causing genes and animal models is extremely important. Knowledge of the disease-causing genes may lead to an understanding of pathways that are critical in maintaining normal function of the eye and perhaps, may identify therapeutic targets for prevention of vision loss.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Visual Sciences C Study Section (VISC)
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Dudley, Peter A
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Jackson Laboratory
Bar Harbor
United States
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Kong, Yang; Naggert, Jürgen K; Nishina, Patsy M (2018) The Impact of Adherens and Tight Junctions on Physiological Function and Pathological Changes in the Retina. Adv Exp Med Biol 1074:545-551
Kong, Yang; Zhao, Lihong; Charette, Jeremy R et al. (2018) An FRMD4B variant suppresses dysplastic photoreceptor lesions in models of enhanced S-cone syndrome and of Nrl deficiency. Hum Mol Genet 27:3340-3352
Chang, Bo; FitzMaurice, Bernard; Wang, Jieping et al. (2018) Spontaneous Posterior Segment Vascular Disease Phenotype of a Mouse Model, rnv3, Is Dependent on the Crb1rd8 Allele. Invest Ophthalmol Vis Sci 59:5127-5139
Charette, Jeremy R; Earp, Sarah E; Bell, Brent A et al. (2017) A mutagenesis-derivedLrp5mouse mutant with abnormal retinal vasculature and low bone mineral density. Mol Vis 23:140-148
Krebs, Mark P (2017) Using Vascular Landmarks to Orient 3D Optical Coherence Tomography Images of the Mouse Eye. Curr Protoc Mouse Biol 7:176-190
Chang, Bo (2016) Mouse Models as Tools to Identify Genetic Pathways for Retinal Degeneration, as Exemplified by Leber's Congenital Amaurosis. Methods Mol Biol 1438:417-30
Chang, Bo (2015) Survey of the nob5 mutation in C3H substrains. Mol Vis 21:1101-5
Maddox, Dennis M; Collin, Gayle B; Ikeda, Akihiro et al. (2015) A Mutation in Syne2 Causes Early Retinal Defects in Photoreceptors, Secondary Neurons, and Müller Glia. Invest Ophthalmol Vis Sci 56:3776-87
Soundararajan, Ramani; Won, Jungyeon; Stearns, Timothy M et al. (2014) Gene profiling of postnatal Mfrprd6 mutant eyes reveals differential accumulation of Prss56, visual cycle and phototransduction mRNAs. PLoS One 9:e110299
Low, Benjamin E; Krebs, Mark P; Joung, J Keith et al. (2014) Correction of the Crb1rd8 allele and retinal phenotype in C57BL/6N mice via TALEN-mediated homology-directed repair. Invest Ophthalmol Vis Sci 55:387-95

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