Photoreceptor death in retinal and macular degenerative diseases is a leading cause of inherited vision loss in developed countries. Novel therapeutic strategies have recently emerged to repair neural circuits affected by photoreceptor (PR) cell loss, including trophic factor delivery to extend the life of dying PRs, gene therapy approaches, and retinal implants designed to capture photons and transmit the electric signals to ganglion cells. Photoreceptors have an intimate relationship with the retinal pigment epithelium (RPE) for exchange of macromolecules, removal of shed membrane discs, and retinoid recycling. An improved understanding of the development of the photoreceptor-RPE complex will allow better design of gene- and cell-based therapies.
To explore the epigenetic contribution to retinal development, Nasonkin’s lab generated conditional knockout alleles of DNA methyltransferase 1 (DNMT1) in mice. Knockdown in early eye development did not produce lamination or cell fate defects (except in cones), but photoreceptors completely lacked outer segments, despite near normal expression of phototransduction and cilia genes. Nasonkin also identified disruption of RPE morphology and polarization, and his results demonstrate a unique function of DNMT1-mediated DNA methylation in retinal development.