Mapping of genetic modifiers of Nr2e3 rd7/rd7 that suppress retinal degeneration and restore blue cone cells to normal quantity.
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 F(1) progeny were intercrossed to produce F(2) mice. In each intercross, 20-24% of the total F(2) 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.
Haider
Neena B
NB
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. nhaidern@unmc.edu
Zhang
Weidong
W
Hurd
Ron
R
Ikeda
Akihiro
A
Nystuen
Arne M
AM
Naggert
Jürgen K
JK
Nishina
Patsy M
PM
D000818:Animals; D003433:Crosses, Genetic; D004843:Epistasis, Genetic; D051379:Mice; D009154:Mutation; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology*; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D013045:Species Specificity
C485736:Nr2e3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear