RESEARCH PROJECTS

Patterning Cone Photoreceptors - Forming Precious ‘Neurocrystals’.  We have a long-standing interest in an intriguing pattern of cones that occur across the back of the retina - a mosaic of cell types patterned with such precision it has been called a ‘neurocrystal’.  How is the neurocrytal nucleated, and once begun, how does the pattern of cones serve as a template for the growing retina to add more cones in the same pattern?  In short, we want to understand how this pattern of cells develop.  This is an especially interesting problem when one considers how little we understand about how cells of different types are positioned relative to one another, and how pervasive and important such relationships may be in the CNS.  Forward genetics and a candidate gene approach have provided insights into cell adhesion and lateral induction pathways we believe to be required in this development.  The function of these cell mosaics remains hypothetical, and the genetic tools we develop, combined with our electrophysiology suite, may allow us insight into this century-old mystery.

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We investigate degeneration and regeneration in the CNS.  Our research framework leads us to ask why it is that mammals have lost the potential to regenerate damaged CNS cells.  We are beginning projects to consider if there is adaptive value in regression of this trait.  Amongst possible ideas, we speculate that regenerative capacity is sacrificed for neural plasticity underpinning learning and memory.  In this regard, we expect that we will synthesize our work regarding regeneration with our research on synaptogenesis-related proteins (APP, PrP, etc) and processes to develop a deep understanding of the factors driving regressive evolution of CNS regeneration.  In the near term, our projects can be broken down as:

Visual Ecology of Fish thru the lens of Zebrafish Genetics.  Many fascinating hypotheses have been proposed as to why photoreceptors have evolved different tuning and patterns across fishes.  These hypotheses centre on adaptations to changing visual tasks.  Famous examples include visually-driven speciation in cichlids and sexual selection in guppys, whereas emerging data highlight intriguing examples such as patterning in Anableps. The genetic tools we are developing in zebrafish allow us to take a large step beyond describing these correlations to now test these hypotheses by altering genes and photoreceptor distributions.  An ongoing research project is allowing us to mimic the ontogeny of UV cones that disappear in salmonids, with exquisite specificity and very informative control experiments. Longer-term goals include deploying our genetic tools, especially transgenesis and gene knockout by zinc finger nucleases, in other fish species beginning with other cyprinids.  Overall, we identify genes that mediate retinal development, compare the control of their expression across species, and manipulate the genes (e.g. to change photoreceptor complement) during tests of visual function. We thus dissect the evolution of the developmental program and also determine the adaptive value of the amazing structures observed.

Functional Cone Photoreceptor Regeneration. Overall we seek to discover and characterize genes that will enable stem cells to be driven toward cone photoreceptors, and to rewire into the remaining neural network.  Two approaches include characterizing mutants with disrupted cone differentiation, and developing precise paradigms of cone ablation to simplify the regenerative response. We are ablating individual cell types, testing candidate genes, developing in vivo cell visualization protocols, and measuring the rewiring of cones using ERGs. Such work has been rewarding in (nocturnal) rodents, enabling regeneration of rod photoreceptors.  We believe the diurnal zebrafish are perfectly situated to derive similar results to regenerate cones, because they have innate stem cells, abundant cones, and excellent genetics. Clinically, we envision this work will contribute to retinal stem cell therapy or activating latent stem cells (Müller glia) that may one day be able to be activated in humans. 

Zebrafish Models of Alzheimer & Prion Disease.  We are creating transgenic zebrafish toward the goal of modelling disease progression.  We seek tractable disease models, or at least in vivo assays of protein function, to enable screening of candidate genes or small molecules as putative therapeutics. We have a goal of creating prion-infectible fish, and have fish systems under containment for this purpose.  A second approach is to explore genetic interactions and familial disease mutations to test hypotheses derived from protein interactome data.  To complete these objectives we have improved upon and successfully deployed zinc finger nucleases, an emerging technique allowing targetted knockout of genes-of-interest.  We also have created a variety of topical transgenic fish.  In the near term we will assess how these genetic manipulations affect disease spread through the CNS and affect synaptogenesis, including through collaborative in vivo electrophysiology approaches.