ABSTRACT: Each year, millions of people lose their vision to chronic degenerative diseases like glaucoma, retinitis pigmentosa, macular degeneration, and diabetic retinopathy. However, therapeutic options for patients are remarkably limited, in part because the biological events underlying these retinopathies are only starting to be understood. Glia can both mitigate and exacerbate neurodegeneration, so understanding neuron-glia crosstalk during chronic stress-induced conditions is an essential first step towards building more effective vision-saving tools. We have developed an experimental pipeline that uncovers functional, cellular and molecular changes during chronic light-induced degeneration and recovery. Our approach takes advantage of two genetically amenable model systems, Drosophila and zebrafish, to probe for evolutionarily deeply conserved, and hence fundamental, neuroprotective responses from endogenous radial glia. Using non-invasive structure-function methods, coupled to histological and single-cell RNAseq studies, we will test for conserved cellular and molecular events associated with recoverable vs irrecoverable light damage. As proof-of-principle, we propose to define the neuroprotective role for the transcription factor prospero (pros)/Prox1 in this experimental paradigm. Pros/Prox1 is a pleiotropic factor implicated in diabetes, neural progenitor cell cycle control, neuron-glia fate decisions, and regeneration in response to acute physical damage. Preliminary and published studies reveal that Pros/Prox1 is enriched in fly and fish retinal glia, and is required to prevent retinal degeneration. The successful completion of this R21 will identify conserved Pros/Prox1-dependent glial response pathways that are at play during light-induced degeneration. In the long-term, these studies will serve as the foundation for developing screens to identify nodes of intervention for chronic retinal degenerative diseases.