A comparative analysis of gene and protein expression in chronic and acute models of photoreceptor degeneration in adult zebrafish

Adult zebrafish are capable of photoreceptor (PR) regeneration following acute phototoxic lesion (AL). We developed a chronic low light (CLL) exposure model that more accurately reflects chronic photoreceptor degeneration observed in many human retinal diseases. Here, we characterize the morphological and transcriptomic changes associated with acute and chronic models of PR degeneration at 8 time points over a 28-day window using immunohistochemistry and 3’mRNA-seq. We first observed a differential sensitivity of rod and cone PRs to CLL. Next, we found no evidence for Müller glia (MG) gliosis or regenerative cell-cycle reentry in the CLL model, which is in contrast to the robust gliosis and proliferative response from resident MG in the AL model. Differential responses of microglia between the models was also observed. Transcriptomic comparisons between the models revealed gene-specific networks of PR regeneration and degeneration, including genes that are activated under conditions of chronic PR stress. Finally, we showed that CLL is at least partially reversible, allowing for rod and cone outer segment outgrowth and replacement of rod cell nuclei via an apparent upregulation of the existing rod neurogenesis mechanism. Collectively, these data provide a direct comparison of the morphological and transcriptomic photoreceptor degeneration and regeneration models in zebrafish. 3'mRNA sequencing of single adult zebrafish retinas harvested at 7 different time-points post chronic exposure to ~5,000 lux "low light" lesion, along with dark adapted 0hr controls (n=6).