The main objective of this project is to add to our understanding of the mechanisms underlying sensory neuron axon guidance during development and regeneration. We recently discovered a gene, beta-3-N-acetyl-glucosaminyltransferase (beta-3GnT1) that is expressed by subsets of sensory neurons in the olfactory epithelium but also by sensory neurons in some cranial ganglia and in dorsal root ganglia. It encodes an enzyme that is key to the synthesis of glycans that terminate in Lactosamine. Beta-3GnT1 expression is essential for the growth and guidance of olfactory neurons to targets in the olfactory bulb. Preliminary evidence suggests that axon guidance is severely perturbed in mice with a null mutation in their beta3GnT1 gene. We will characterize the loss of function mutations of beta-3GnT1 in the main olfactory system, using odorant receptor reporter mice. We will also isolate and analyze the structure of lactosamine containing proteins. Olfactory tissues contain members of a family of proteins called galectins that bind to Lactosamine and are thought to be involved in adhesive and signaling functions through these Lactosamine-containing proteins. We will analyze the binding of galectins to olfactory proteins that express Lactosamine and study guidance defects in galectin knockout mice. Furthermore we will analyze the unique ability of the main olfactory system to regenerate and to determine the role that Lactosamine/galectin interactions plays in this process. Preliminary studies show that vomeronasal axon guidance is also perturbed in beta-3GnT1 mutant mice, thus we will analyze the role of Lactosamine in development of vomeronasal connections to the accessory olfactory bulb using vomeronasal receptor reporter mice. These studies will shed new light on molecules and mechanisms shared during development of sensory systems and lead to further insights into the molecular and cellular biology of olfactory perception, particularly the recovery of olfactory function following injury.Project Narrative: This project will shed light on the function of a complex glycan that is required for development of the olfactory system. In addition, as a model for spontaneous regeneration, these studies are likely to broaden our understanding of potential treatments for peripheral nerve injury and neurodegenerative disease. ? ? ?
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