Abstract
Purpose: :
The establishment of an array of neuronal cells is influenced by spatially and temporally specified gene expression during development. Polymorphisms within genes that modulate proliferation and fate determination may play a role in the natural variation of cell number in the vertebrate retina. We are seeking such polymorphic genes that are responsible for the phenotypic variation in cone photoreceptor cell number within the mouse retina. To determine the loci modulating this trait, we employed quantitative trait loci (QTL) mapping using recombinant inbred (RI) strains of mice.
Methods: :
Retinas were immunolabeled for cone photoreceptor outer segments using cone opsin antibodies. The total number of cone photoreceptors was estimated by sampling fields at 1mm intervals across the retinal surface in the A/J (A) and C57BL6/J (B6) parental strains and in the 26 RI strains derived from them (the AXB/BXA RI strain-set). QTL analysis was performed using the WebQTL mapping module of GeneNetwork (www.genenetwork.org).
Results: :
There are approximately 197,000 cone photoreceptors in the B6 strain, while the A strain has 41% fewer, totaling 116,000. This difference in cell number is also seen across the RI strains, spanning the range of the parental strains. The variance was modest within any of the strains relative to the overall variation between the strains, the heritability estimate for this trait being 0.67. We mapped a significant QTL to the proximal end of chromosome 10, where the presence of two B alleles contributes 27% of the overall difference in cone photoreceptor number between the A and B6 strains. We have identified a particular candidate gene of interest at the peak of the QTL, Myb (20.81 Mb), a transcriptional coactivator expressed in the embryonic mouse retina and maintained in photoreceptors into maturity. Myb has been shown, in other cell types, to control proliferation and differentiation during development.
Conclusions: :
A polymorphic gene or genes on the proximal portion of Chr 10 contributes to the natural variation in cone photoreceptor number in the mouse retina. Myb is a prime candidate gene at this QTL. Future studies will examine the variation in Myb gene expression, the presence of SNPs within this gene, and the effects of Myb conditional gene knock-out.
Keywords: retinal development • gene mapping • photoreceptors