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Patrick Keeley, Irene Whitney, Benjamin Reese; A Locus on Chromosome 11 Regulates Spacing of Cholinergic Amacrine Cells in the Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2496. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Neurons of the same type are often spaced in nonrandom mosaics across the retina, driven during development to avoid proximity to neighboring like-type cells through a variety of mechanisms, such as tangential migration and selective cell death. The genes that control these processes in specific retinal populations, however, have until recently gone largely unexplored. We previously observed that the regularity of the cholinergic amacrine cell mosaic in the inner nuclear layer showed conspicuous variation across different inbred strains of mice. We therefore investigated the genetic control of this trait by using a panel of recombinant inbred (RI) mouse strains.
112 mice from the 25 RI strains of the AXB/BXA strain-set, as well as the A/J (A) and C57BL/6J (B6) parental strains, were analyzed, using a minimum of three mice per strain. Wholemount retinas were immunostained using antibodies to ChAT, revealing the population of cholinergic amacrine cells. Four central and four peripheral fields per retina were analyzed: for each field, the x-y coordinates of each cell were recorded and the nearest neighbor regularity index (NNRI) was calculated. Quantitative trait loci (QTL) mapping was performed at GeneNetwork (genenetwork.org).
The average NNRI varied across the RI strains, with a 45% increase from lowest to highest strain (BXA7: 3.37; BXA11: 4.90), but showed meager variation within each strain, with an average CoV of 0.07. Mapping revealed a significant QTL on chromosome 11 where B6 alleles increased trait values by 0.50, a value over one-third of the variation across the strains. This QTL was validated using a chromosome substitution strain, in which the A haplotype for chromosome 11 had been introgressed on a B6 background, as they exhibited a significant decrease in NNRI of 0.58 when compared to B6 controls. 54 genes underlie the QTL peak on chromosome 11, 34 of which harbor genetic variants between the parental strains. Of those 34 candidates, 21 are known to be expressed in the retina during development.
A genetic variant between A and B6 mice exists on chromosome 11 that alters the spacing of cholinergic amacrine cells. Ongoing analysis is investigating candidate genes and the role they might play in establishing nonrandom cellular mosaics.
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