Correct functioning of the visual system requires axonal connections from eye to brain to develop with precisely-defined spatial order. The broad long-term objective of our studies is to identify cell-cell signaling molecules, and characterize their functions and mechanisms of action in guiding the precise development of visual axonal connections. The proposal focuses on retinal ganglion cell axons, and their projections to the tectum, a retinal axon target which has long been a major model system.
Aim 1 proposes to study novel molecular interactions in the retinotectal system. The Amyloid Precursor Protein (APP) is a cell surface molecule with important roles in Alzheimer's pathology, but its normal functions are not well understood. APP has long been proposed to act as a cell surface ligand or receptor. In preliminary studies, binding partners for APP have been identified and are prominently expressed in the retinotectal system. Studies will be continued into the molecular interactions of these proteins, and their effects on APP signaling and retinal axon growth and development.
Aim 2 is to study mechanisms of tectal gradient formation. Ephrins are known to act as graded positional labels for axon mapping in the tectum. However, the mechanisms that initially set up these gradients are not well understood. Studies will be continued to identify the steps in the upstream molecular hierarchy that initially convert a non-graded to a graded distribution, and to identify biochemical mechanisms for gradient formation in the tectum.
Aim 3 is to characterize RNA-based mechanisms for regulation in retinal axons. Evidence has accumulated to show that regulated protein synthesis occurs within axons and can have important functions. This has opened up an exciting new field of study, but the mechanisms remain poorly characterized. RNA-based regulation mechanisms will be studied in retinal ganglion cell axons, including the location and dynamics of synthesis, and mechanisms for regulated translation of mRNAs in response to extracellular cues. While our primary goal is to elucidate basic molecular mechanisms, the work has broader implications for disease. APP is important for its roles in Alzheimer's disease, including pathology of the retina. Identification of ligands that regulate APP processing may lead to therapeutic targets to inhibit production of beta amyloid. More generally, studies to identify and characterize novel cell-cell signaling cues in the visual system, may lead to therapeutic agents for maintenance, repair or regeneration of visual connections.
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