Spatiotemporal pattern of rod degeneration in the S334ter-line-3 rat model of retinitis pigmentosa

Abstract

We have recently described the surviving cones and Müller-glia process remodeling in retinitis pigmentosa (RP) and shown that rod degeneration triggers the reorganization of the cone mosaic into an orderly array of rings. Within these rings, remodeled Müller-glia processes envelope cones. Here, we report the spatiotemporal pattern of healthy rods, their relationship with dying rods and the way that rod death stimulates the modification of cone spatial-distribution patterns and Müller-glia processes in the S334ter-line-3 rat, a transgenic model expressing a rhodopsin mutation that causes RP. The spatial patterns of rods, cones, microglial and Müller cells were labeled by immunocytochemistry with cell-type-specific markers at various stages of deveopment in rat whole-mount retinas. Spatial patterns of dying cells were examined by TUNEL staining. The S334ter rod mosaic began to develop small holes around postnatal day 10. These hot-spots of cell death progressively increased in size, leaving larger rod-less holes behind. The holes were temporarily occupied by active microglial cells, before being replaced by remodeled Müller-cell processes. Our data suggest that the hot spots of rod death create holes in the rod mosaic early in retinal degeneration and that the resulting pattern triggers the modification of the spatial-distribution patterns of cones and glia cells.

Mathematical models of retinitis pigmentosa: The oxygen toxicity hypothesis

“…The retinal geometry ensures that θ 2 − θ 1 ≤ O(1). We note that the case where θ 2 − θ 1 = O( ) matches well with the patch widths measured in the rat by García-Ayuso et al (2013); Ji et al (2012); Zhu et al (2013), which lie in the (non-dimensional) range 3.8 × 10 −3 -1.9 × 10 −2 . We decompose the domain into outer and inner regions.…”

“…However, less common forms exist, in which rod and cone loss occurs on the same timescale, or in which cone loss precedes rod loss (termed a cone-rod dystrophy; Hartong et al, 2006). Histological data from humans and rats suggest that the initial loss of photoreceptors occurs in roughly circular patches which expand and coalesce over time (Cideciyan et al, 1998;García-Ayuso et al, 2013;Ji et al, 2012;Lee et al, 2011;Zhu et al, 2013). Whilst the initial loss of photoreceptors is due directly to a mutation, it is not known what causes degenerate patches to spread, or what causes cone loss to follow rod loss in the rod-cone dystrophy form (and vice-versa in the cone-rod dystrophy form).…”

Inhibition of Matrix Metalloproteinase 9 Enhances Rod Survival in the S334ter-line3 Retinitis Pigmentosa Model

“…In RP, rhodopsin S334ter-line3 (S334ter) rat retina, rods die in “clusters” [30–32], suggesting inductive cell death mechanisms consistent with animal models and human studies demonstrating that degenerating rods often lead to deaths of immediate neighbors [33–35]. Recently, we discovered Tissue Inhibitor of Metalloproteinase 1 (TIMP-1) restores the cone mosaic and protects cone outer segments at later stages of retinal degeneration in S334ter-line3 retina [32, 36, 37].…”

“…Recently, we discovered Tissue Inhibitor of Metalloproteinase 1 (TIMP-1) restores the cone mosaic and protects cone outer segments at later stages of retinal degeneration in S334ter-line3 retina [32, 36, 37]. Although TIMP-1 influences MMP activity, it specifically binds to and inhibits MMP-9 activation [38].…”

Reactive Muller Glia as Potential Retinal Progenitors

“…In some respects, the Müller glia are expanding into areas where degenerating neurons and/or axonal processes are found, such as the subretinal space or plexiform layers [204]. If these new processes persist, the end result is the formation of scar tissue, which can permanently block the reattachment of the retina, regeneration of outer segments or regeneration of synaptic contacts in the plexiform layers [118,122,[205][206][207][208][209]. The extension of processes onto the vitreal surface of the retina results in the formation of periretinal membranes that may under epithelial to mesenchymal transformation into myofibrocytes that spread and become contractile [210].…”