Lazy eyes zebrafish mutation affects Muller glial cells, compromising photoreceptor function and causing partial blindness

A behavioral assay based on the optokinetic reflex was used to screen chemically mutagenized zebrafish larvae for deficits in visual function. A homozygous recessive mutation, lazy eyes (lze), was isolated based on the observation that 5-day postfertilization (dpf) mutants displayed weaker and less frequent eye movements than wild-type fish in response to moving stripes. Electroretinographic (ERG) recordings revealed that mutants had severely reduced a- and b-wave amplitudes relative to wild-type fish, indicating outer retinal dysfunction. Retinal lamination and cellular differentiation were normal in the lze retina; however, mutant photoreceptor cells had small outer segments and pyknotic nuclei were occasionally observed in the outer retina and the marginal zone of lze. Cone, rod, amacrine, bipolar, and Muller cell marker analyses indicated that the typical lze retina contained fewer rod photoreceptors and fewer Muller cells than wild-type fish at 5 dpf. At 3 dpf, however, mutant retinas had normal numbers of rod photoreceptors and Muller cells, suggesting that the initial differentiation of these cell types occurred normally. Rod photoreceptor histology was normal at this early stage, but Muller cells were often hypertrophied, suggesting that they were unhealthy. Constant light rearing of mutant animals accelerated the Muller cell degeneration, severely worsened the visual deficit, but had no obvious affect on the photoreceptors. When ERG responses and Muller cell degeneration from the same mutant animals were analyzed, the extent of the Muller cell loss matched closely the degree to which ERG responses were reduced. In summary, the Ize gene appears to be required for Muller cell viability and normal visual function. The lze mutant may be a model for the study of the involvement of Muller cells in photoreceptor development and function.