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The Journal of Neuroscience, October 1, 1999, 19(19):8603-8615

Genetic Disorders of Vision Revealed by a Behavioral Screen of 400 Essential Loci in Zebrafish

Stephan C. F. Neuhauss¹, Oliver Biehlmaier³, Mathias W. Seeliger², Tilak Das⁴, Konrad Kohler³, William A. Harris⁴, and Herwig Baier⁵

¹ Max-Planck-Institut für Entwicklungsbiologie, Abteilung Physikalische Biologie, D-72076 Tübingen, Germany, ² Department II and ³ Experimentelle Ophtalmologie, University Eye Hospital, 72076 Tübingen, Germany, ⁴ Department of Anatomy, Cambridge University, Cambridge CB2 3DY, United Kingdom, and ⁵ University of California, San Francisco, Department of Physiology, Programs in Neuroscience, Genetics, and Human Genetics, San Francisco, California 94143-0444

We examined optokinetic and optomotor responses of 450 zebrafish mutants, which were isolated previously based on defects in organ formation, tissue patterning, pigmentation, axon guidance, or other visible phenotypes. These strains carry single point mutations in >400 essential loci. We asked which fraction of the mutants develop blindness or other types of impairments specific to the visual system. Twelve mutants failed to respond in either one or both of our assays. Subsequent histological and electroretinographic analysis revealed unique deficits at various stages of the visual pathway, including lens degeneration (bumper), melanin deficiency (sandy), lack of ganglion cells (lakritz), ipsilateral misrouting of axons (belladonna), optic-nerve disorganization (grumpy and sleepy), inner nuclear layer or outer plexiform layer malfunction (noir, dropje, and possibly steifftier), and disruption of retinotectal impulse activity (macho and blumenkohl). Surprisingly, mutants with abnormally large or small eyes or severe wiring defects frequently exhibit no discernible behavioral deficits. In addition, we identified 13 blind mutants that display outer-retina dystrophy, making this syndrome the single-most common cause of inherited blindness in zebrafish. Our screen showed that a significant fraction (~5%) of the essential loci also participate in visual functions but did not reveal any systematic genetic linkage to particular morphological traits. The mutations uncovered by our behavioral assays provide distinct entry points for the study of visual pathways and set the stage for a genetic dissection of vertebrate vision.

Key words: visual system; vision; retina; tectum; optomotor; optokinetic; albinism; photoreceptor; retinal ganglion cell; outer-retina dystrophy; retinitis pigmentosa; retinal degeneration; mutant screen; mutation; zebrafish; Danio rerio; forward genetics; ERG

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19198603-13$05.00/0

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