PURPOSE. To investigate the impact of progressive age-related photoreceptor degeneration on retinal integrity in Stargardt-like macular dystrophy (STGD3). METHODS. The structural design of the inner retina of the ELOVL4 transgenic mouse model of STGD3 was compared with that of age-matched littermate wild-type (WT) mice from 1 to 24 months of age by using immunohistofluorescence and confocal microscopy and by relying on antibodies against cell-type-specific markers, synapse-associated proteins, and neuro-transmitters. RESULTS. Muller cell reactivity occurred at the earliest age studied, before photoreceptor loss. This finding is perhaps not surprising, considering the cell's ubiquitous roles in retina homeostasis. Second-order neurons displayed salient morphologic changes as a function of photoreceptoral input loss. Age-related sprouting of dendritic fibers from rod bipolar and horizontal cells into the ONL did not occur. In contrast, with the loss of photoreceptor sensory input, these second-order neurons progressively bore fewer synapses. After rod loss, the few remaining cones showed abnormal opsin expression, revealing tortuous branched axons. After complete ONL loss (beyond 18 months of age), localized areas of extreme retinal disruptions were observed in the central retina. RPE cell invasion, dense networks of strongly reactive Muller cell processes, and invagination of axons and blood vessels were distinctive features of these regions. In addition, otherwise unaffected cholinergic amacrine cells displayed severe perturbation of their cell bodies and synaptic plexi in these areas. CONCLUSIONS. Remodeling in ELOVL4 transgenic mice follows a pattern similar to that reported after other types of hereditary retinopathies in animals and humans, pointing to a potentially common pathophysiologic mechanism. (Invest Ophthalmol Vis Sci. 2010;51:2248-2262) DOI:10.1167/iovs.09-4718
机构:
N Carolina State Univ, Dept Anim Sci, Raleigh, NC 27695 USAUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Sommer, Jeffrey R.
Estrada, Jose L.
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N Carolina State Univ, Dept Anim Sci, Raleigh, NC 27695 USA
N Carolina State Univ, Dept Mol Biomed Sci, Raleigh, NC 27695 USA
Indiana Univ, Dept Surg, Indianapolis, IN 46204 USAUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Estrada, Jose L.
Collins, Edwin B.
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N Carolina State Univ, Dept Anim Sci, Raleigh, NC 27695 USAUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Collins, Edwin B.
Bedell, Matthew
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Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Shiley Eye Ctr, La Jolla, CA 92093 USA
Sichuan Univ, Mol Med Res Ctr, Chengdu 610064, Peoples R China
Sichuan Univ, Dept Ophthalmol, W China Hosp, Chengdu 610064, Peoples R ChinaUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Bedell, Matthew
Alexander, Curtis A.
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N Carolina State Univ, Dept Anim Sci, Raleigh, NC 27695 USAUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Alexander, Curtis A.
Yang, Zhenglin
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Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Shiley Eye Ctr, La Jolla, CA 92093 USAUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Yang, Zhenglin
Hughes, Guy
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Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Shiley Eye Ctr, La Jolla, CA 92093 USAUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Hughes, Guy
Mir, Bashir
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N Carolina State Univ, Dept Mol Biomed Sci, Raleigh, NC 27695 USAUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Mir, Bashir
Gilger, Brian C.
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N Carolina State Univ, Dept Clin Sci, Raleigh, NC 27695 USAUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Gilger, Brian C.
Grob, Seanna
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Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Shiley Eye Ctr, La Jolla, CA 92093 USAUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Grob, Seanna
Wei, Xinran
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Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Shiley Eye Ctr, La Jolla, CA 92093 USA
Sichuan Univ, Mol Med Res Ctr, Chengdu 610064, Peoples R China
Sichuan Univ, Dept Ophthalmol, W China Hosp, Chengdu 610064, Peoples R ChinaUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Wei, Xinran
Piedrahita, Jorge A.
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N Carolina State Univ, Dept Mol Biomed Sci, Raleigh, NC 27695 USAUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Piedrahita, Jorge A.
Shaw, Peter X.
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Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Shiley Eye Ctr, La Jolla, CA 92093 USA
Sichuan Univ, Mol Med Res Ctr, Chengdu 610064, Peoples R China
Sichuan Univ, Dept Ophthalmol, W China Hosp, Chengdu 610064, Peoples R ChinaUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Shaw, Peter X.
Petters, Robert M.
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N Carolina State Univ, Dept Anim Sci, Raleigh, NC 27695 USAUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Petters, Robert M.
Zhang, Kang
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Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
Univ Calif San Diego, Shiley Eye Ctr, La Jolla, CA 92093 USA
Sichuan Univ, Mol Med Res Ctr, Chengdu 610064, Peoples R China
Sichuan Univ, Dept Ophthalmol, W China Hosp, Chengdu 610064, Peoples R ChinaUniv Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
机构:
Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Ophthalmol, 81 Iron Ro, Seoul 06351, South KoreaSungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Ophthalmol, 81 Iron Ro, Seoul 06351, South Korea
Kim, Jong Min
Lee, Chung
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Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Samsung Genome Inst, Seoul, South Korea
Sungkyunkwan Univ, SAIHST, Dept Hlth Sci & Technol, Seoul, South KoreaSungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Ophthalmol, 81 Iron Ro, Seoul 06351, South Korea
Lee, Chung
Lee, Ga-In
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Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Ophthalmol, 81 Iron Ro, Seoul 06351, South KoreaSungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Ophthalmol, 81 Iron Ro, Seoul 06351, South Korea
Lee, Ga-In
Kim, Nayoung K. D.
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Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Samsung Genome Inst, Seoul, South KoreaSungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Ophthalmol, 81 Iron Ro, Seoul 06351, South Korea
Kim, Nayoung K. D.
Ki, Chang-Seok
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Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Lab Med & Genet, Seoul, South KoreaSungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Ophthalmol, 81 Iron Ro, Seoul 06351, South Korea
Ki, Chang-Seok
Park, Woong-Yang
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Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Samsung Genome Inst, Seoul, South Korea
Sungkyunkwan Univ, Sch Med, Dept Mol Cell Biol, Seoul, South KoreaSungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Ophthalmol, 81 Iron Ro, Seoul 06351, South Korea
Park, Woong-Yang
Kim, Byoung Joon
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Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Neurol, Seoul, South KoreaSungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Ophthalmol, 81 Iron Ro, Seoul 06351, South Korea
Kim, Byoung Joon
Kim, Sang Jin
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Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Ophthalmol, 81 Iron Ro, Seoul 06351, South KoreaSungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Ophthalmol, 81 Iron Ro, Seoul 06351, South Korea