Genetic ablation of the DNA demethylation pathway in retinal progenitor cells impairs photoreceptor development and function, leading to retinal dystrophy

Abstract

AbstractRod and cone photoreceptors are critical for vision, and their loss leads to blindness. We explored the role of epigenetic mechanisms in photoreceptor development and function that is still poorly understood. To this end, we created mice in which the DNA demethylation pathway was inactivated in retinal progenitor cells (RPCs). We have shown that DNA demethylation caused by the activity of TET oxidases is necessary during the differentiation of RPCs into photoreceptors. Disruption of the TET-dependent DNA demethylation pathway prevents the proper expression of genes necessary for photoreceptor development and function (e.g.,Rho, Nr2e3, Prph2, Pde6a, Pde6b, Pde6g, Cplx4, Grk1, Cnga1, Cngb1, Cplx4). The result of this is underdevelopment or complete absence of outer segments and synaptic termini in photoreceptors of TET-deficient retinas, resulting in loss of rod and cone function, as assayed by electroretinogram. The number of photoreceptors decreases in the TET-deficient retinas over time, leading to retinal dystrophy.