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D.L. Stenkamp, K. Muhunthan; Age–Related Abnormalities of Cone Photoreceptors in a Zebrafish Model . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1688.
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Purpose: The underlying causes and risk factors for age–related macular degeneration (AMD) are genetically complex and there is a paucity of animal models for understanding its etiology. Photoreceptor cell death is likely secondary to defects in the retinal pigmented epithelium (RPE). Here we explore the potential for a zebrafish model for AMD, in zebrafish carrying mutant sonic–you+/– (syu+/–) alleles of the sonic hedgehog gene. This gene encodes a signaling protein that is released by the RPE and is required for photoreceptor differentiation and survival (Stenkamp et al., 2000; 2002). Methods: Reproductively mature (10 months), and reproductively senescent (2 years and 2+ years) zebrafish of two genotypically wildtype strains and two syu+/– strains were used in this study. Cryosectioned eyes were evaluated for cone photoreceptor loss by indirect immunofluorescence with the zpr–1 cone marker, and contralateral whole–mounted retinas were subjected to in situ hybridization with a blue cone opsin riboprobe. Because zebrafish have the capacity to replace lost retinal tissue throughout life, cone pattern was qualitatively assessed as an indicator of a regenerative process (see Stenkamp et al., 2001) that may mask cone loss. Results: In whole–mounted material, certain retinal phenotypes were found to be specific to reproductively senescent syu+/– zebrafish, and were not found in other experimental tissues. These phenotypes included a patchy loss of cone photoreceptors and an irregular cone pattern, suggesting an ongoing degeneration/regeneration process. However, in sectioned material, cone loss or abnormality was evident in fewer than half of the reproductively senescent syu+/– zebrafish examined. Conclusions: The syu+/– zebrafish may present an opportunity to understand processes that result in age–related cone loss, as well as mechanisms for cone replacement that can take place amid underlying pathology. The Hedgehog signaling pathway may represent a novel genetic and pharmacological target for AMD research and treatment.
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