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Mapping of genetic modifiers of Nr2e3 rd7/rd7 that suppress retinal degeneration and restore blue cone cells to normal quantity

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Abstract

The retinal degeneration 7 (rd7) mouse, lacking expression of the Nr2e3 gene, exhibits retinal dysplasia and a slow, progressive degeneration due to an abnormal production of blue opsin-expressing cone cells. In this study we evaluated three strains of mice to identify alleles that would slow or ameliorate the retinal degeneration observed in Nr2e3 rd7/rd7 mice. Our studies reveal that genetic background greatly influences the expression of the Nr2e3 rd7/rd7 phenotype and that the inbred mouse strains CAST/EiJ, AKR/J, and NOD.NON-H2 nb1 carry alleles that confer resistance to Nr2e3 rd7/rd7-induced retinal degeneration. B6.Cg-Nr2e3 rd7/rd7 mice were outcrossed to each strain and the F1 progeny were intercrossed to produce F2 mice. In each intercross, 20–24% of the total F2 progeny were homozygous for the Nr2e3 rd7/rd7 mutation in a mixed genetic background; approximately 28–48% of the Nr2e3 rd7/rd7 homozygotes were suppressed for the degenerative retina phenotype in a mixed genetic background. The suppressed mice had no retinal spots and normal retinal morphology with a normal complement of blue opsin-expressing cone cells. An initial genome scan revealed a significant association of the suppressed phenotype with loci on chromosomes 8 and 19 with the CAST/EiJ background, two marginal loci on chromosomes 7 and 11 with the AKR/J background, and no significant QTL with the NOD.NON-H2 nb1 background. We did not observe any significant epistatic effects in this study. Our results suggest that there are several genes that are likely to act in the same or parallel pathway as NR2E3 that can rescue the Nr2e3 rd7/rd7 phenotype and may serve as potential therapeutic targets.

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Acknowledgments

This study was supported by grants from the National Eye Institute [EY11996 (PMN), NRSA postdoctoral training grant (F32 EY07080–01A (NBH)], the Center for Biomedical Excellence Award through the National Center for Research Resources, National Institutes of Health [NIH 5 P20 RRO18788–02 (NBH)], and the Nebraska Tobacco Settlement Biomedical Research Development, TJL Cancer Core Grant (CA-34196).

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Authors and Affiliations

  1. Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA

    Neena B. Haider & Arne M. Nystuen

  2. Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA

    Neena B. Haider

  3. The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine, 04609, USA

    Weidong Zhang, Ron Hurd, Jürgen K. Naggert & Patsy M. Nishina

  4. Department of Genetics, University of Wisconsin, Madison, Wisconsin, 53706, USA

    Akihiro Ikeda

  5. 985805 Nebraska Medical Center, Omaha, NE, 68198-5805, USA

    Neena B. Haider

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  1. Neena B. Haider
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  7. Patsy M. Nishina
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Correspondence to Neena B. Haider.

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Haider, N.B., Zhang, W., Hurd, R. et al. Mapping of genetic modifiers of Nr2e3 rd7/rd7 that suppress retinal degeneration and restore blue cone cells to normal quantity. Mamm Genome 19, 145–154 (2008). https://doi.org/10.1007/s00335-008-9092-2

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