EVOLUTION OF NEURODEGENERATION AND OTHER SPECIALIZATIONS IN THE VERTEBRATE VISUAL SYSTEM

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MECHANISMS AND HISTORY OF CHORDATE EYE EVOLUTION AND REGRESSION Our recent focus is on Pacific Hagfish to understand evolution of the vertebrate eye. Other cyclostomes (lampreys) and all vertebrates share a camera-style eye, thus the Hagfish (oft-reported to lack of eyes/vision) are positioned perfectly to understand the appearance of the vertebrate eye over evolutionary time. Our study of rarely-examined young Pacific Hagfish reveals novel compelling arguments that hagfish possess almost all features of a vertebrate eye, and a pineal gland; this will codify hagfish eyes as functional, though degenerating during ontogeny (not paedomorphic), and rewrite the textbook version of early chordate eye evolution. Inspired by eye degeneration in cavefish (regressive evolution), we theorize that eyes in hagfish degenerate for adaptive reasons. We are now using adult zebrafish mutants that lack eyes (troglomorphic zebrafish!), that we developed as a model of human juvenile photoreceptor degeneration, to test ultimate hypotheses of cavefish and hagfish visual system evolution. We will answer unique questions by assessing fish that are in the very earliest stages of evolving to survive an eyeless phenotype. DEVELOPMENT and FUNCTION of CONE PHOTORECEPTOR MOSAICS – Cone photoreceptors of fishes are similar in morphology and function compared to other vertebrates, yet have a striking pattern in their distribution: The four cone classes (UV-, blue-, green- & red-sensitive) are arranged in a ‘mosaic’ similar to an elaborate checkerboard and reminiscent of Drosophila ommatidia. The development and function (and thus evolution) of this striking pattern remain mysterious, and several variants have been identified in differing fish species. Pathways identified to date by forward genetics support the hypothesis that lateral induction and differential adhesion are involved in cone mosaic formation. Such hypotheses will be analyzed in zebrafish using our world-class expertise in targeted mutagenesis, and by expression of protein variants in specific cone classes. The roles of cell-cell interactions in this system will be queried using novel transgenic zebrafish allowing conditional ablation of cone photoreceptor subtypes. REGRESSIVE EVOLUTION of UV SENSITIVITY – Most fishes have substantial visual sensitivity to ultraviolet light. This sensitivity can decrease during ontogeny, as has been indentified in salmon and trout associated with their migrations. Leading hypotheses regarding adaptive value of this loss assume decreasing function of UV sensitivity in larger animals with different visual tasks. Zebrafish have been engineered to test a novel alternate hypothesis that the disappearance of UV-sensitive cones enhances performance in some visually-mediated tasks. Zebrafish have been engineered such that photoreceptor classes can be conditionally ablated or inactivated. These fish will be assessed in electrophysiology and behavioural paradigms to evaluate visual functions including wavelength discrimination. SYNTHESIS. Going forward, I have begun to integrate these three themes under an overarching umbrella. Ask not ‘Why can fish regenerate their eyes and CNS?’ but more productively ask ‘Why have mammals lost the capacity to regenerate their eyes and CNS?’. We assume CNS regeneration is adaptive. I will apply Regressive Evolution theory to inform hypotheses on the adaptive value of losing CNS regeneration. My working hypothesis is that genes involved in stem cells/regeneration have been co-opted in mammals for new functions including synaptic plasticity, learning and memory. Experimentally manipulating these genes in adult basal vertebrates is a core of our rare ability to perform targeted mutagenesis in zebrafish.