The early response of rods and cones to retinal degeneration: the role of EGR1 in photoreceptor death

Luca Merolla

Retinitis pigmentosa is a large heterogeneous group of inherited retinal diseases and the major cause of blindness in children and working-age adults worldwide. The causes of this disease are linked to different genetic mutations, mostly in rod-specific genes. Expression of these genes triggers a cascade of cell death affecting rod photoreceptors first, and later also cone photoreceptors, eventually leading to complete blindness. Droplet-based single-cell RNA sequencing (scRNA-seq) on the rd10 model of retinitis pigmentosa identified two major waves of rod degeneration: an early phase, characterised by the strong and transient induction of Early Growth Response 1 (Egr1), and a later phase characterised by the equally strong induction of Cebpd. Since Egr1 was strongly upregulated also in degenerating cones, EGR1 may have a key regulatory function in degenerative events.

The aim of this project is to describe the role of Egr1 in the degenerating retina and define its implications on photoreceptors survival in vivo. To reach this goal, we will modulate its expression levels specifically in rods and/or cones via transgenic methods, such as RNA interference and gene overexpression. We will deliver the respective gene constructs using AAV virus particles that we inject into the subretinal space of Rho^P23H/+mice, a model of adRP. Since this model has a slower degenerative phenotype, the time window for delivery and assessment of the treatments is wider. Based on preliminary data and on previous research, EGR1 expression in dying photoreceptors seems to be shared by different degenerative models, suggesting that the activation of the gene is not model-specific but may be common to retinal degenerative events. Therefore, understanding EGR1 functions and mechanisms of action is of great interest and may yield valuable insights on retinal degenerative processes, as well as the identification of factors downstream EGR1 that could serve as pharmacological targets to alleviate degeneration.