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M. A. Raven, I. E. Whitney, R. W. Williams, B. E. Reese; Regulation of Dopaminergic Amacrine Cell Number in the Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5688.
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The number of dopaminergic (DA) amacrine cells is tightly controlled despite comprising less than one-hundredth of a percent of the total number of neurons in a mature mouse retina. The present analysis has examined the variation in size of this neuronal population across various laboratory and recombinant inbred strains of mice to understand the regulation of DA cell number.
Five different laboratory strains of mice (ALS, ALR, A/J and C57BL/6J and C57BL/6NCrl) and twenty-four recombinant inbred (RI) strains derived from the A/J and C57BL/6J (B6) strains were examined for the total number of DA cells. Retinas were immunolabeled using a primary antibody to tyrosine hydroxylase, and the entire retinal wholemount was sampled in three to eight mice in every strain.
The five laboratory strains showed a nearly four-fold variation in DA cell number, with the A/J strain having the fewest (249 cells) while the ALS strain had the most (962 cells). The ALR strain had 732 cells and the B6 strain from Jackson had 621 cells, while that from Charles River had 470 cells. Individual RI strains from the AxB/BxA strain set had average numbers of DA cells that spanned the range between those two parental strains. The variation in cell number between RI strains was unrelated to either the age of the animals, or to total retinal area. Within any given strain, variance in total cell number was meager, with the standard deviation being about 5% of the strain average. A broad QTL for DA cell number was identified on chromosome 7 centered at 71.9Mb. To confirm the presence of a gene or genes on chromosome 7 for which A alleles reduce total DA cell number, consomic B6.A<7> mice were also examined, in which all chromosome 7 genes contain A alleles in an otherwise B6 genetic background. As expected, these mice showed fewer DA amacrine cells than did B6 mice, having 509 cells.
Potential genes in this QTL include the pigmentation-associated genes tyr and p, and the cell survival-associated genes Ntrk3 and bax. While DA cell number correlates with coat color, tyr can be ruled out, because a point mutation rendering this gene non-functional (in c2J mice) does not reduce DA cell number. Interestingly, bcl2-overexpressing mice have a nearly ten-fold increase in DA cells, directing attention to bax, a pro-apoptotic member of the bcl2 family of genes.
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