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Felix L Struebing, Rebecca King, Allison Ashley-Koch, Michael A Hauser, R Rand Allingham, Eldon E Geisert; Interval mapping reveals a quantitative trait locus controlling retinal ganglion cell number in mice. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3660.
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© ARVO (1962-2015); The Authors (2016-present)
The inherent number of retinal ganglion cells (RGCs) appears to be under genetic control and may be a risk factor for glaucoma (Carnes et al. 2014, PLoS Genetics), meaning that individuals with a lower RGC number may be at higher risk for the development of glaucoma. We used a systems biology approach to identify quantitative trait loci (QTLs) modulating RGC number in the BXD recombinant inbred (RI) strain set.
BXD mice between 100 to 120 days of age were deeply anesthetized and perfused intracardially with 2% Paraformaldehyde and 2.5% Glutaraldehyde. Optic nerves were embedded in plastic, sectioned at 0.8 µm for light microscopy and stained with p-phenylenediamine. Nerves were photographed at 10X magnification to determine the cross-sectional area of the nerve. A second series of photographs were taken at 60X and used to systematically count axons with the aid of the iPad application ImagePad®. The total number of axons in each nerve was calculated and these counts were averaged per strain. The averages were used to create a mapping file and quantitative trait analysis was performed with the bioinformatic tools found on www.genenetwork.org. Candidate genes were evaluated by cross-referencing QTLs with risk alleles in the human NEIGHBOR/GLAUGEN GWAS dataset.
A total of 138 nerves were counted in 37 strains. The mean number of axons per nerve was 55,604 (SE 1289, range of 37,150 to 78,480). In the genome wide interval map there was one significant QTL related to retinal ganglion cell number with a peak on proximal chromosome 3 between 10 and 26 Mb. We have named this locus retinal ganglion cell number 1 (Regan1). In addition to that, a suggestive QTL was found on distal chromosome 7 from 142 to 145 Mb. Three SNPs near the CPA3 (Carboxypeptidase A3) locus were associated with POAG risk in the NEIGHBOR/GLAUGEN dataset (peak SNP rs1356258; p=4.3X10-4).
These data from the BXD RI strains demonstrate that retinal ganglion cell number is under genetic control. Interval mapping of the data reveals a new genomic locus, Regan1, which modulates RGC number. Future experiments will define the genomic elements or candidate genes in Regan1 controlling RGC number, a potential risk factor for glaucoma.
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