In humans, various genetic defects or age-related diseases, such as diabetic retinopathies, glaucoma, and macular degeneration, cause the death of retinal neurons and profound vision loss. One approach to treating these diseases is to utilize stem and progenitor cells to replace neurons in situ, with the expectation that new neurons will create new synaptic circuits or integrate into existing ones. Reprogramming non-neuronal cells in vivo into stem or progenitor cells is one strategy for replacing lost neurons. Zebrafish have become a valuable model for investigating cellular reprogramming and retinal regeneration. This review summarizes our current knowledge regarding spontaneous reprogramming of Müller glia in zebrafish and compares this knowledge to research efforts directed toward reprogramming Müller glia in mammals. Intensive research using these animal models has revealed shared molecular mechanisms that make Müller glia attractive targets for cellular reprogramming and highlighted the potential for curing degenerative retinal diseases from intrinsic cellular sources.

Brain injury activates complex inflammatory signals in dying neurons, surviving neurons, and glia. Here, we establish that inflammation regulates the regeneration of photoreceptors in the zebrafish retina and determine the cellular expression and function of the inflammatory protease, matrix metalloproteinase 9 (Mmp‐9), during this regenerative neurogenesis. Following photoreceptor ablation, anti‐inflammatory treatment suppresses the number of injury‐induced progenitors and regenerated photoreceptors. Upon photoreceptor injury, mmp‐9 is induced in Müller glia and Müller glia‐derived photoreceptor progenitors. Deleting mmp‐9 results in over production of injury‐induced progenitors and regenerated photoreceptors, but over time the absence of Mmp‐9 compromises the survival of the regenerated cones. At all time‐points studied, the levels of tnf‐α are significantly elevated in mutant retinas. Anti‐inflammatory treatment in mutants rescues the defects in cone survival. These data provide a link between injury‐induced inflammation in the vertebrate CNS, Mmp‐9 function during neuronal regeneration and the requirement of Mmp‐9 for the survival of regenerated cones.

Purpose. To report a novel mouse model of achromatopsia with a cpfl3 mutation found in the ALS/LtJ strain. methods. The effects of a cpfl3 mutation were documented using fundus photography, electroretinography (ERG), and histopathology. Genetic analysis was performed using linkage studies and PCR gene identification. results. Homozygous cpfl3 mice had poor cone-mediated responses on ERG at 3 weeks that became undetectable by 9 months. Rod-mediated waveforms were initially normal, but declined with age. Microscopy of the retinas revealed progressive vacuolization of the photoreceptor outer segments. Immunocytochemistry with cone-specific markers showed progressive loss of labeling for α-transducin, but the cone outer segments in the oldest mice examined remained intact and positive with peanut agglutinin (PNA). The cpfl3 mapped to mouse chromosome 3 at the same location as human GNAT2, known to cause achromatopsia. Sequence analysis revealed a missense mutation due to a single base pair substitution in exon 6 in cpfl3. conclusions. The Gnat2 ^cpfl3 mutation leads to cone dysfunction and the progressive loss of cone α-transducin immunolabeling. Despite a poor cone ERG signal and loss of cone α-transducin label, the cones survive at 14 weeks as demonstrated by PNA staining. This mouse model of achromatopsia will be useful in the study of the development, pathophysiology, and treatment of achromatopsia and other cone degenerations. The gene symbol for the cpfl3 mutation has been changed to Gnat2 ^cpfl3 .