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Invest Ophthalmol Vis Sci. 2014 Nov 20;56(1):164-76. doi: 10.1167/iovs.14-15479.

Genetic background and light-dependent progression of photoreceptor cell degeneration in Prominin-1 knockout mice.

Author information

1
Ocular Biology and Therapeutics Unit (ORBIT), Faculty of Brain Sciences, UCL Institute of Ophthalmology, University College London, London, United Kingdom.
2
Laboratory for Cell Lineage Modulation, RIKEN Center for Developmental Biology (CDB), Kobe, Japan.
3
Laboratory for Cell Lineage Modulation, RIKEN Center for Developmental Biology (CDB), Kobe, Japan Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.

Abstract

PURPOSE:

Mutations in the Prominin-1 (Prom1) gene are known to cause retinitis pigmentosa and Stargardt disease, both of which are associated with progressive photoreceptor cell death. There are no effective therapies for either disorder. The aim of this study was to investigate the mechanism of the retinal degeneration in Prom1-deficient mouse models.

METHODS:

We constructed Prom1 knockout mice with two distinct genetic backgrounds of C57BL/6 and C57BL/6xCBA/NSlc, and investigated the photoreceptor degeneration by means of histology and functional tests.. In addition, we examined the effect of light on the Prom1(-/-) retina by rearing the mice in the normal light/dark cycle and completely dark conditions. Finally, we investigated if the retinoic-acid derivative Fenretinide slowed the pace of retinal degeneration in these mouse models.

RESULTS:

The Prom1(-/-)-knockout mice with both backgrounds developed photoreceptor degeneration after eye opening, but the CB57/BL6-background mice developed photoreceptor cell degeneration much faster than the C57BL/6xCBA/NSlc mice, demonstrating genetic background dependency.. Interestingly, our histologic and functional examination showed that the photoreceptor cell degeneration of Prom1-knockout mice was light-dependent, and was almost completely inhibited when the mutant mice were kept in the dark. The Prom1-knockout retina showed strong downregulation of expression of the visual cycle components, Rdh12 and Abca4. Furthermore, administration of Fenretinide, which lowers the level of the toxic lipofuscin, slowed the degeneration of photoreceptor cells.

CONCLUSIONS:

These findings improve our understanding of the mechanism of cell death in Prominin-1-related disease and provide evidence that fenretinide may be worth studying in human disease.

KEYWORDS:

Prominin-1; Stargardt disease; fenretinide; light; modifier gene; photoreceptor degeneration; retinitis pigmentosa

PMID:
25414197
DOI:
10.1167/iovs.14-15479
[Indexed for MEDLINE]

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