Development, degeneration, and circuitry of the vertebrate retina
We are interested in the mechanisms that direct development and degeneration of the central nervous system (CNS) of vertebrates. We are focussing our studies on the vertebrate retina, a relatively simple and well-characterized area of the CNS. We have used genomics approaches to determine genes that are candidates for a role in cell fate determination. We are now trying to determine how the retina uses this large repetoire of genes to form this complex tissue of >60 neuronal cell types. To aid in these studies, we also carry out lineage studies wherein we mark individual progenitor cells in vivo, and analyze the types of neurons produced. Of interest is whether progenitor cells produce cells that are connected in various types of retinal circuits. To this end, and more generally to discover the circuitry of CNS neurons, we have recently developed novel viral vectors which move transsynaptically in vivo. These vectors can be modified to transmit either retrogradely or anterogradely, and can be used to transduce a variety of genes, encoding fluorescent proteins, ion channels, or calcium indicators. We are interested in their applications in neuroscience, as well as what they can tell us about how viruses transmit among neurons. We are also using them to learn more about retinal circuitry.
We are also interested in the mechanisms that lead to the death of photoreceptors in the many inherited forms of human blindness. We have found that we can slow down the death of these cells through administration of insulin, whereas the death is accelerated if animals are depleted for insulin. In addition, we have found that delivery of the histone deacetylase 4 gene can slow down the autonomous death of mutant rod photoreceptors. We are now investigating whether gene therapy approaches that follow from these findings might extend vision in animal models, with the goal of developing a therapy for humans.