The common forms of vision loss occur because retinal ganglion cells (RGCs) undergo apoptosis and necrosis in the retina. Apoptosis, however, is not as dangerous to the surrounding tissue as necrosis. Apoptotic cell death stimulates the production of anti-inflammatory and neuroprotective factors from immune cells that have internalized apoptotic cells (Fig. 1A). Our studies indicate that therapeutic strategies based on mimicking a systemic increase in levels of apoptotic signals can significantly reduce retinal injury. In contrast, endogenous factors (proteins, RNA, DNA, etc.; known as damage-associated molecular patterns or DAMPs) liberated from necrotic cells mediate cytotoxic, pro-inflammatory responses in retinal tissue (Fig. 1A). We demonstrated that these DAMPs, spilled from necrotic cells, cause inflammation and retinal damage. We also found that suppressing neuronal necrosis in the retina promotes a neuroprotective environment and reduces tissue damage. Thus, in contrast to apoptosis, necrosis can trigger further RGC death and retinal damage. Historically viewed as an entirely accidental and unregulated cellular event, we now know that necrosis, like apoptosis, can be regulated and executed by programmed mechanisms (Fig. 1B). We demonstrated that regulated necrosis contributes to retinal injury through direct loss of RGCs and induction of associated inflammatory responses. Since RGC necrosis is executed via signaling cascades and can be regulated, a better understanding of its molecular mechanisms could lead to discovery of innovative therapeutic strategies for preventing vision loss in patients with retinal neurodegenerative disease. The effectiveness of some of these therapies has already been demonstrated in our published studies.

Understanding the mechanisms of retinal development is of vital importance in the proposal of therapeutic approaches to restoring visual function via the regeneration of lost retinal neurons. An ideal reparative strategy would be for the retina to heal itself—an inherent characteristic of many species, but not one usually associated with mammals. Adult teleost fish, such as zebrafish, and amphibians have an outstanding self-healing ability to regenerate damaged retinas and restore lost sight. Retinal regeneration in these species relies on two different cell types: Müller glia (MG, teleost fish) and retinal pigment epithelium (RPE, amphibians). MG and RPE undergo a reprogramming process allowing them to generate progenitors for retinal regeneration after injury. Why teleost fish and amphibians have the ability to reprogram MG and RPE after injury, while mammals do not, remains a mystery. We investigated the epigenetic plasticity of RPE and MG to identify possible mechanisms that prevent mammalian RPE and MG from reprogramming and differentiating into retinal neurons. Our published data suggest that epigenetic mechanisms play an essential role in this process.

Though much progress has been made in the understanding of signaling cascades driving retinal development and pathology, the role of epigenetic mechanisms remains to be explored as meticulously. To fill this gap, we evaluated the contribution of the DNA methylation and DNA demethylation pathways to retinal development and pathology in recent studies (Fig. 3). We discovered that the promoters (a region of DNA where the transcription of a gene is initiated) of many mutated in retinitis pigmentosa (RP) and related photoreceptor dystrophies genes were highly methylated (hypermethylated) in DNA isolated from fetal retinas and retinal progenitor cells (RPCs; e.g., USH2A, RHO, PRPH2, EYS, AIPL1, CNGB1, IMPG1, IMPG2, NR2E3, PDE6A, PDE6G, PDE6C, PDE6H, RBP3, RP1). The methylation of these promoters was significantly reduced during RPC differentiation into photoreceptors and accompanied by an increased expression of the corresponding genes. It is generally accepted that DNA methylation in promoter regions silences gene expression, while DNA demethylation should occur to allow gene expression. Hence, unsuccessful demethylation of the promoters of the genes listed above during RPC differentiation into photoreceptors may reduce or even eliminate their activity, leading to photoreceptor dystrophies without any mutations in the genomic DNA (Fig. 4). Thus, not only mutations in DNA but also retina-specific epigenetic changes in the DNA may contribute to the pathogenesis of RP and related diseases, indicating the importance of understanding the DNA demethylation pathway during photoreceptor development. The ten–eleven translocation (TET) protein family has a vital role in DNA demethylation and regulates eye development and neurogenesis in various species. Our data and the results of other laboratories indicate that the TET-dependent DNA demethylation pathway controls photoreceptor development. The objectives of this project are to gain a detailed understanding of how the TET-driven DNA demethylation pathway specifies the differentiation of RPCs into photoreceptors, and to investigate how irregularities in its activity lead to photoreceptor death and retinal degeneration.