Inner Retina Remodeling in a Mouse Model of Stargardt-like Macular Dystrophy (STGD3)

被引:16
|
作者
Kuny, Sharee [1 ]
Gaillard, Frederic [2 ]
Mema, Silvina C. [1 ]
Freund, Paul R. [1 ]
Zhang, Kang [3 ]
MacDonald, Ian M. [1 ]
Sparrow, Janet R. [4 ]
Sauve, Yves [1 ]
机构
[1] Univ Alberta, Dept Ophthalmol, Edmonton, AB T6G 2H7, Canada
[2] Univ Poitiers, CNRS, IPBC, UMR 6187, Poitiers, France
[3] Univ Calif San Diego, Dept Ophthalmol, La Jolla, CA 92093 USA
[4] Columbia Univ, Dept Ophthalmol, New York, NY 10027 USA
基金
加拿大健康研究院; 美国国家卫生研究院;
关键词
FIBRILLARY ACIDIC PROTEIN; PHOTORECEPTOR CELL DEGENERATION; PIGMENT EPITHELIAL-CELLS; ROD BIPOLAR CELLS; BINDING PROTEIN; FUNCTIONAL ABNORMALITIES; MAMMALIAN RETINA; HORIZONTAL CELLS; GENE-EXPRESSION; NULL MUTATION;
D O I
10.1167/iovs.09-4718
中图分类号
R77 [眼科学];
学科分类号
100212 ;
摘要
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
引用
收藏
页码:2248 / 2262
页数:15
相关论文
共 45 条
  • [31] Production of ELOVL4 transgenic pigs: a large animal model for Stargardt-like macular degeneration
    Sommer, Jeffrey R.
    Estrada, Jose L.
    Collins, Edwin B.
    Bedell, Matthew
    Alexander, Curtis A.
    Yang, Zhenglin
    Hughes, Guy
    Mir, Bashir
    Gilger, Brian C.
    Grob, Seanna
    Wei, Xinran
    Piedrahita, Jorge A.
    Shaw, Peter X.
    Petters, Robert M.
    Zhang, Kang
    BRITISH JOURNAL OF OPHTHALMOLOGY, 2011, 95 (12) : 1749 - 1754
  • [32] CLINICAL-FEATURES OF A STARGARDT-LIKE DOMINANT PROGRESSIVE MACULAR DYSTROPHY WITH GENETIC-LINKAGE TO CHROMOSOME 6Q
    STONE, EM
    NICHOLS, BE
    KIMURA, AE
    WEINGEIST, TA
    DRACK, A
    SHEFFIELD, VC
    ARCHIVES OF OPHTHALMOLOGY, 1994, 112 (06) : 765 - 772
  • [33] Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease
    Raz-Prag, Dorit
    Ayyagari, Radha
    Fariss, Robert N.
    Mandal, Md Nawajes A.
    Vasireddy, Vidyullatha
    Majchrzak, Sharon
    Webber, Andrea L.
    Bush, Ronald A.
    Salem, Norman, Jr.
    Petrukhin, Konstantin
    Sieving, Paul A.
    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2006, 47 (08) : 3603 - 3611
  • [34] Stargardt-like macular dystrophy protein ELOVL4 exerts a dominant negative effect by recruiting wild-type protein into aggresomes
    Vasireddy, V
    Vijayasarathy, C
    Huang, JB
    Wang, XFF
    Jablonski, MM
    Petty, HR
    Sieving, PA
    Ayyagari, R
    MOLECULAR VISION, 2005, 11 (78-79): : 665 - 676
  • [35] Identification of the PROM1 Mutation p.R373C in a Korean Patient With Autosomal Dominant Stargardt-like Macular Dystrophy
    Kim, Jong Min
    Lee, Chung
    Lee, Ga-In
    Kim, Nayoung K. D.
    Ki, Chang-Seok
    Park, Woong-Yang
    Kim, Byoung Joon
    Kim, Sang Jin
    ANNALS OF LABORATORY MEDICINE, 2017, 37 (06) : 536 - 539
  • [36] Elovl4 5-bp deletion knock-in mouse model for Stargardt-like macular degeneration demonstrates accumulation of ELOVL4 and lipofuscin
    Vasireddy, Vidyullatha
    Jablonski, Monica M.
    Khan, Naheed W.
    Wang, Xiao Fei
    Sahu, Priya
    Sparrow, Janet R.
    Ayyagari, Radha
    EXPERIMENTAL EYE RESEARCH, 2009, 89 (06) : 905 - 912
  • [37] Evaluation of the ELOVL4 gene in a Chinese family with autosomal dominant STGD3-like macular dystrophy
    Lai, Z
    Zhang, XN
    Zhou, W
    Yu, R
    Le, YP
    JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 2005, 9 (04) : 961 - 965
  • [38] Whole exome sequencing identifies a novel splice-site mutation in IMPG2 gene causing Stargardt-like juvenile macular dystrophy in a north Indian family
    Chatterjee, Souradip
    Gupta, Shashank
    Chaudhry, Vidya Nair
    Chaudhry, Prashaant
    Mukherjee, Ashim
    Mutsuddi, Mousumi
    GENE, 2022, 816
  • [39] A novel gene for autosomal dominant Stargardt-like macular dystrophy with homology to the SUR4 protein family involved in very long chain fatty acid synthesis.
    Ritter, RL
    Donoso, LA
    Edwards, AO
    AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 69 (04) : 617 - 617
  • [40] Autosomal dominant Stargardt-like macular dystrophy: I. Clinical characterization, longitudinal follow-up, and evidence for a common ancestry in families linked to chromosome 6q14
    Edwards, AO
    Miedziak, A
    Vrabec, T
    Verhoeven, J
    Acott, TS
    Weleber, RG
    Donoso, LA
    AMERICAN JOURNAL OF OPHTHALMOLOGY, 1999, 127 (04) : 426 - 435