Long-Term Retinal Cone Survival and Delayed Alteration of the Cone Mosaic in a Transgenic Mouse Model of Stargardt-Like Dystrophy (STGD3)

Abstract

Photoreceptor degeneration in this STGD3 mouse model follows the time course of a slow rod-cone dystrophy. The cone mosaic is preserved for almost 1 year after the onset of rod loss. This long delay provides an opportunity to examine rod-cone interactions during retinal degeneration and to test therapeutic effectiveness at protracting cone dysfunction.

Number and Distribution of Mouse Retinal Cone Photoreceptors: Differences between an Albino (Swiss) and a Pigmented (C57/BL6) Strain

“…It has been previously reported [8] , [15] , [16] , [18] that cones that express the L opsin, are preferentially found in the dorsal retina. Our topographical analysis shows that this is not so.…”

“…This is important as it lays the basis for further research in cone degenerative paradigms, which is currently a topic of extensive research. In general, mutants [22] or transgenic [15] mice have a pigmented background whereas studies on phototoxic cone death are carried out in albino mice [32] .…”

Number and Distribution of Mouse Retinal Cone Photoreceptors: Differences between an Albino (Swiss) and a Pigmented (C57/BL6) Strain

“…It has been previously reported [8] , [15] , [16] , [18] that cones that express the L opsin, are preferentially found in the dorsal retina. Our topographical analysis shows that this is not so.…”

“…This is important as it lays the basis for further research in cone degenerative paradigms, which is currently a topic of extensive research. In general, mutants [22] or transgenic [15] mice have a pigmented background whereas studies on phototoxic cone death are carried out in albino mice [32] .…”

Optimization-Based Pairwise Interaction Point Process (O-PIPP): A Precise and Universal Retinal Mosaic Modeling Approach

“…One key research area involves exploring the correlation between photoreceptor mosaic changes and visual function in disease states by combining in vivo retinal imaging and visual function tests. 46 – 50 Similar studies on animals 9 , 51 , 52 can more easily recruit ex vivo techniques. In this paper, we have demonstrated how O-PIPP provides a supplementary approach to exploring the underlying mechanisms between abnormal retinal structure and visual function loss.…”

Early Onset Ultrastructural and Functional Defects in RPE and Photoreceptors of a Stargardt-Like Macular Dystrophy (STGD3) Transgenic Mouse Model

“…Stable ratios of mutant ELOVL4 to endogenous Elovl4 over more than 10 generations of breeding allowed us to make objective correlations between former 12,20,38 and present work. The proportion of mutant ELOVL4 over endogenous Elovl4 increases as retinal degeneration progresses in TG.…”

“…Although introduced in all photoreceptors, the presence of the human mutant ELOVL4 protein impacts cones much later in degeneration (as in human STGD3), when at least half of the rod complement is lost. 20 The distinctive vulnerability of rods (comprising~98% of the mouse retina, compared with an average close to 95% in humans) is due, at least in part, to a precarious combination of high disc DHA content (the most oxidizable fatty acid; required for disc membrane fluidity) and extremely high oxygen levels (required for passive diffusion in an avascular environment), 50 both of which are modulated by the constant turnover of their outer segment discs. Rod function (as opposed to cone) was first affected in TG (P30).…”

Number and Distribution of Mouse Retinal Cone Photoreceptors: Differences between an Albino (Swiss) and a Pigmented (C57/BL6) Strain

“…It has been previously reported [8] , [15] , [16] , [18] that cones that express the L opsin, are preferentially found in the dorsal retina. Our topographical analysis shows that this is not so.…”

“…This is important as it lays the basis for further research in cone degenerative paradigms, which is currently a topic of extensive research. In general, mutants [22] or transgenic [15] mice have a pigmented background whereas studies on phototoxic cone death are carried out in albino mice [32] .…”

Optimization-Based Pairwise Interaction Point Process (O-PIPP): A Precise and Universal Retinal Mosaic Modeling Approach

“…One key research area involves exploring the correlation between photoreceptor mosaic changes and visual function in disease states by combining in vivo retinal imaging and visual function tests. 46 – 50 Similar studies on animals 9 , 51 , 52 can more easily recruit ex vivo techniques. In this paper, we have demonstrated how O-PIPP provides a supplementary approach to exploring the underlying mechanisms between abnormal retinal structure and visual function loss.…”

Early Onset Ultrastructural and Functional Defects in RPE and Photoreceptors of a Stargardt-Like Macular Dystrophy (STGD3) Transgenic Mouse Model

“…Stable ratios of mutant ELOVL4 to endogenous Elovl4 over more than 10 generations of breeding allowed us to make objective correlations between former 12,20,38 and present work. The proportion of mutant ELOVL4 over endogenous Elovl4 increases as retinal degeneration progresses in TG.…”

“…Although introduced in all photoreceptors, the presence of the human mutant ELOVL4 protein impacts cones much later in degeneration (as in human STGD3), when at least half of the rod complement is lost. 20 The distinctive vulnerability of rods (comprising~98% of the mouse retina, compared with an average close to 95% in humans) is due, at least in part, to a precarious combination of high disc DHA content (the most oxidizable fatty acid; required for disc membrane fluidity) and extremely high oxygen levels (required for passive diffusion in an avascular environment), 50 both of which are modulated by the constant turnover of their outer segment discs. Rod function (as opposed to cone) was first affected in TG (P30).…”

Number and Distribution of Mouse Retinal Cone Photoreceptors: Differences between an Albino (Swiss) and a Pigmented (C57/BL6) Strain

“…It has been previously reported [8] , [15] , [16] , [18] that cones that express the L opsin, are preferentially found in the dorsal retina. Our topographical analysis shows that this is not so.…”

“…This is important as it lays the basis for further research in cone degenerative paradigms, which is currently a topic of extensive research. In general, mutants [22] or transgenic [15] mice have a pigmented background whereas studies on phototoxic cone death are carried out in albino mice [32] .…”

Optimization-Based Pairwise Interaction Point Process (O-PIPP): A Precise and Universal Retinal Mosaic Modeling Approach

“…One key research area involves exploring the correlation between photoreceptor mosaic changes and visual function in disease states by combining in vivo retinal imaging and visual function tests. 46 – 50 Similar studies on animals 9 , 51 , 52 can more easily recruit ex vivo techniques. In this paper, we have demonstrated how O-PIPP provides a supplementary approach to exploring the underlying mechanisms between abnormal retinal structure and visual function loss.…”

Early Onset Ultrastructural and Functional Defects in RPE and Photoreceptors of a Stargardt-Like Macular Dystrophy (STGD3) Transgenic Mouse Model

“…Stable ratios of mutant ELOVL4 to endogenous Elovl4 over more than 10 generations of breeding allowed us to make objective correlations between former 12,20,38 and present work. The proportion of mutant ELOVL4 over endogenous Elovl4 increases as retinal degeneration progresses in TG.…”

“…Although introduced in all photoreceptors, the presence of the human mutant ELOVL4 protein impacts cones much later in degeneration (as in human STGD3), when at least half of the rod complement is lost. 20 The distinctive vulnerability of rods (comprising~98% of the mouse retina, compared with an average close to 95% in humans) is due, at least in part, to a precarious combination of high disc DHA content (the most oxidizable fatty acid; required for disc membrane fluidity) and extremely high oxygen levels (required for passive diffusion in an avascular environment), 50 both of which are modulated by the constant turnover of their outer segment discs. Rod function (as opposed to cone) was first affected in TG (P30).…”