Distinct nuclear localization patterns of DNA methyltransferases in developing and mature mammalian retina

Abstract

DNA methyltransferases--DNMT1, DNMT3a, and DNMT3b--produce methylation patterns that dynamically regulate chromatin remodeling and gene expression. The vertebrate retina provides an ideal model to elucidate molecular control of neurogenesis as all neuronal cell types and Müller glia are generated in a conserved order from common pools of progenitor cells. As a prelude to exploring epigenetic regulation of mammalian retinal development, we investigated the expression of Dnmt1, Dnmt3a, and Dnmt3b in the mouse retina from embryonic day (E) 10.5 to 10 months of age. High levels of transcripts for all three Dnmt genes were observed in early stages of retinal differentiation, with significantly reduced expression after birth. Although DNMT1 protein is abundant in retinal progenitors at E10.5, it becomes restricted to postmitotic cells by E15.5. Most cells in the postnatal retina show nuclear immunostaining of DNMT1; however, the photoreceptors exhibit distinctive patterns. In rods, weak expression of DNMT1 is detected in perinuclear region and in the nucleus, whereas a strong nuclear labeling is evident in cones. DNMT3a and DNMT3b show a discrete pattern in developing retina with high expression at E11.5, little or no immunostaining by E15.5, and then postnatal expression overlapping with DNMT1 in early born neurons (ganglion, amacrine and horizontal cells, and cones). Robust nuclear localization of DNMTs in cones compared to rods suggests a potential role of DNA methylation in differential remodeling of chromatin in these two specialized neurons. Our studies indicate that DNA methyltransferases contribute to the establishment and maturation of cell fates during retinal development.