Retinal proliferation response in the buphthalmic zebrafish, bugeye

The zebrafish retina regenerates in response to acute retinal lesions, replacing damaged neurons with new neurons. In this study we test the hypothesis that chronic stress to inner retinal neurons also triggers a retinal regeneration response in the bugeye zebrafish. Mutations in the lrp2 gene in zebrafish are associated with a progressive eye phenotype (bugeye) that models several risk factors for human glaucoma including buphthalmos (enlarged eyes), elevated intraocular pressure (IOP), and upregulation of genes related to retinal ganglion cell pathology. The retinas of adult bugeye zebrafish showed high rates of ongoing proliferation which resulted in the production of a small number of new retinal neurons, particularly photoreceptors. A marker of mechanical cell stress, Hsp27, was strongly expressed in inner retinal neurons and glia of bugeye retinas. The more enlarged eyes of individual bugeye zebrafish showed disrupted retinal lamination, and a persistent reduced density of neurons in the ganglion cell layer (GCL), although total numbers of GCL neurons were higher than in control eyes. Despite the presence of a proliferative response to damage, the adult bugeye zebrafish remained behaviorally blind. These findings suggest the existence of an unsuccessful regenerative response to a persistent pathological condition in the bugeye zebrafish.

► Retinas of the buphthalmic, adult bugeye zebrafish show high rates of ongoing proliferation.
► Adult bugeye retinas regenerate some new neurons.
► Some adult bugeye retinas show profound disorganization.
► Adult bugeye retinas show evidence of mechanical cell stress to inner retinal neurons.
► Regenerative responses to pathology in adult bugeye do not restore visual function.