Delineating the conserved fundamental processes of photoreceptor differentiation and the maintenance of neuronal identity will be applicable to and required for developing therapeutic interventions for both retinal and neuronal degenerative diseases. To date, the molecular networks required for specifying neuronal cell types, including photoreceptors, have been investigated thoroughly, but the molecular and cellular mechanisms that promote and maintain photoreceptor identity remain poorly understood. Our proposed work utilizes the paradigm of Glass mediated differentiation. Our recent results demonstrate that Glass choreographs the expression of a network of genes required for all aspects of photoreceptor differentiation. Thus this research leverages the genetic strengths of Drosophila neuronal development to investigate and reveal mechanisms required for the differential assembly, functional maturity, and maintenance of photoreceptor synapses. As such:
Aim 1 will test our working hypothesis that the Glass downstream target neto2, encoding an evolutionary conserved accessory protein of kainate receptors, is required for the assembly of the photoreceptor synapses and integrity of the photoreceptors.
Aim 2 investigates and determines the molecular basis of and the functional significance of the interaction between Neto proteins and kainate receptors with respect to assembly of synapses and maintaining photoreceptor integrity. Lastly, Aim 3 develops an innovative inducible methodology that will permit the investigation whether retinal degeneration in neto2 mutant animals is due to defects in synapse formation or homeostasis. Ultimately, medicine's goal of advanced techniques for rehabilitation in cases of replacement, degeneration or injury is contingent on an understanding of the various effects of genetic and environmental perturbations on neuronal differentiation. The proposed research will establish foundational knowledge of photoreceptor differentiation that will have widespread impacts on understanding and developing treatments for numerous diseases from retinal degeneration to epilepsy to neuropathic pain.
The proposed research will utilize an experimental neuronal model to investigate photoreceptor differentiation, in particular synaptogenesis. The proposed research is relevant to public health and the mission of the National Eye Institute because understanding the differentiation of retinal neurons is critical for expanding and implementing therapies for correcting retinal congenital defects and intervening in and preventing retinal degeneration.
