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.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-K (03))
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Davis, Barry
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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Henion, Timothy R; Schwarting, Gerald A (2014) N-linked polylactosamine glycan synthesis is regulated by co-expression of ?3GnT2 and GCNT2. J Cell Physiol 229:471-8
Henion, Timothy R; Madany, Pasil A; Faden, Ashley A et al. (2013) ?3GnT2 null mice exhibit defective accessory olfactory bulb innervation. Mol Cell Neurosci 52:73-86
Knott, Thomas K; Madany, Pasil A; Faden, Ashley A et al. (2012) Olfactory discrimination largely persists in mice with defects in odorant receptor expression and axon guidance. Neural Dev 7:17
Schwarting, Gerald A; Henion, Timothy R (2011) Regulation and function of axon guidance and adhesion molecules during olfactory map formation. J Cell Biochem 112:2663-71
Henion, Timothy R; Faden, Ashley A; Knott, Thomas K et al. (2011) ?3GnT2 maintains adenylyl cyclase-3 signaling and axon guidance molecule expression in the olfactory epithelium. J Neurosci 31:6576-86
Schwarting, Gerald A; Henion, Timothy R (2008) Olfactory axon guidance: the modified rules. J Neurosci Res 86:11-7
Schwarting, Gerald A; Gridley, Thomas; Henion, Timothy R (2007) Notch1 expression and ligand interactions in progenitor cells of the mouse olfactory epithelium. J Mol Histol 38:543-53
Henion, Timothy R; Schwarting, Gerald A (2007) Patterning the developing and regenerating olfactory system. J Cell Physiol 210:290-7
Schwarting, Gerald A; Henion, Timothy R; Nugent, J David et al. (2006) Stromal cell-derived factor-1 (chemokine C-X-C motif ligand 12) and chemokine C-X-C motif receptor 4 are required for migration of gonadotropin-releasing hormone neurons to the forebrain. J Neurosci 26:6834-40
Henion, Timothy R; Raitcheva, Denitza; Grosholz, Robert et al. (2005) Beta1,3-N-acetylglucosaminyltransferase 1 glycosylation is required for axon pathfinding by olfactory sensory neurons. J Neurosci 25:1894-903

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