Cone Degeneration Following Rod Ablation in a Reversible Model of Retinal Degeneration

Department of Ophthalmology, Center for Vision Research, SUNY Eye Institute, Upstate Medical University, Syracuse, NY 13210, USA.
Investigative ophthalmology & visual science (Impact Factor: 3.4). 01/2011; 52(1):364-73. DOI: 10.1167/iovs.10-5347
Source: PubMed


Amphibian retinas regenerate after injury, making them ideal for studying the mechanisms of retinal regeneration, but this leaves their value as models of retinal degeneration in question. The authors asked whether the initial cellular changes after rod loss in the regenerative model Xenopus laevis mimic those observed in nonregenerative models. They also asked whether rod loss was reversible.
The authors generated transgenic X. laevis expressing the Escherichia coli enzyme nitroreductase (NTR) under the control of the rod-specific rhodopsin (XOP) promoter. NTR converts the antibiotic metronidazole (Mtz) into an interstrand DNA cross-linker. A visually mediated behavioral assay and immunohistochemistry were used to determine the effects of Mtz on the vision and retinas of XOPNTR F1 tadpoles.
NTR expression was detected only in the rods of XOPNTR tadpoles. Mtz treatment resulted in rapid vision loss and near complete ablation of rod photoreceptors by day 12. Müller glial cell hypertrophy and progressive cone degeneration followed rod cell ablation. When animals were allowed to recover, new rods were born and formed outer segments.
The initial secondary cellular changes detected in the rodless tadpole retina mimic those observed in other models of retinal degeneration. The rapid and synchronous rod loss in XOPNTR animals suggested this model may prove useful in the study of retinal degeneration. Moreover, the regenerative capacity of the Xenopus retina makes these animals a valuable tool for identifying the cellular and molecular mechanisms at work in lower vertebrates with the remarkable capacity of retinal regeneration.

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Available from: Gustav A Engbretson
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    • "In the mouse, expression of NTR driven by the control elements of the human CD2 locus has allowed to induce an extensive and specific T cell depletion in thymus and spleen (Drabek et al., 1997). More recently, transgenic expression of NTR has been successfully used in zebrafish and Xenopus to induce temporally controlled cell specific ablation of cardiomyocytes, pancreatic beta-cells, hepatocytes and rod photoreceptors (Curado et al., 2007; Pisharath et al., 2007; Curado et al., 2008; Choi et al., 2011). Here, we demonstrate that the same experimental strategy can be exploited to eliminate oligodendrocytes in a temporal-and spatial-specific manner in a transgenic Xenopus tadpole. "
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    ABSTRACT: Live imaging studies of the processes of demyelination and remyelination have so far been technically limited in mammals. We have thus generated a Xenopus laevis transgenic line allowing live imaging and conditional ablation of myelinating oligodendrocytes throughout the CNS. In these transgenic pMBP-eGFP-NTR tadpoles the myelin basic protein (MBP) regulatory sequences, specific to mature oligodendrocytes, are used to drive expression of an eGFP (enhanced green fluorescent protein) reporter fused to the Escherichia coli nitroreductase (NTR) selection enzyme. This enzyme converts the innocuous prodrug metronidazole (MTZ) to a cytotoxin. Using two-photon imaging in vivo, we show that pMBP-eGFP-NTR tadpoles display a graded oligodendrocyte ablation in response to MTZ, which depends on the exposure time to MTZ. MTZ-induced cell death was restricted to oligodendrocytes, without detectable axonal damage. After cessation of MTZ treatment, remyelination proceeded spontaneously, but was strongly accelerated by retinoic acid. Altogether, these features establish the Xenopus pMBP-eGFP-NTR line as a novel in vivo model for the study of demyelination/remyelination processes and for large-scale screens of therapeutic agents promoting myelin repair.
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    • "Indeed, when tadpoles at stage 50 were exposed to mtz, their rods started to die soon after the treatment. Furthermore, when mtz treatment was prolonged, cone degeneration was also observed following rod cell death, a characteristic of RP (Choi et al., 2011). Importantly, upon mtz removal, newly born rods were observed in a time-range of thirty days, indicating successful regeneration of death cells. "

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    ABSTRACT: This study evaluated the capacity of Xenopus laevis retina to regenerate photoreceptor cells after cyclic light-mediated acute rod photoreceptor degeneration in a transgenic P23H mutant rhodopsin model of retinits pigmentosa. After discontinuation of cyclic light exposure, we monitored histologic progression of retinal regeneration over a 3 week recovery period. To assess their metabolomic states, contralateral eyes were processed for computational molecular phenotyping. We found that retinal degeneration in the P23H rhodopsin mutation could be partially reversed, with regeneration of rod photoreceptors recovering normal morphology (including full-length rod outer segments) by the end of the 3 week recovery period. In contrast, retinal degeneration mediated by directly induced apoptosis did not recover in the 3 week recovery period. Dystrophic rod photoreceptors with truncated rod outer segments were identified as the likely source of rod photoreceptor regeneration in the P23H retinas. These dystrophic photoreceptors remain metabolically active despite having lost most of their outer segments.
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