The fundamental event during the differentiation of a peripheral olfactory neuron is the selective expression of one allele of one olfactory receptor (OR) gene from among the 1296 members of the superfamily of OR genes. The choice of OR will determine the stimulus sensitivity of the neuron and will determine where that neuron should send its axon, although the means by which the OR directs axon targeting is still poorly understood. This grant proposes to answer 3 fundamental questions about OR choice. 1) Precisely how does OR choice reflect spatial location in the olfactory epithelium? Preliminary evidence suggests that the conventional 4-zone model relating OR expression to location is insufficient. We will take advantage of the explosion of genomic information to test specific hypotheses relating OR family membership and chromosomal location to the pattern of expression. 2) Where does the memory of spatial position reside that allows reconstitution of OR expression after injury? We will transplant progenitor cells into foreign parts of the epithelium to see whether the progenitor cells encode a memory for place or whether cues that derive from the local environment direct expression. 3) How does OR choice govern axonal connectivity during the course of epithelial reconstitution and neuronal regeneration? Data gathered during the prior period of support suggests that recapitulation of the precise one OR-one glomerulus organization occurs during the recovery from extensive peripheral lesion only when a substantial population of pre-existing axons are spared. We will take advantage of strains of mutant mice in which expression of an OR is coincident with expression of a marker protein to extend our analysis of the consequences of mild, moderate, and severe lesions of the periphery. The data obtained will allow us to determine whether fasciculation of growing axons with spared like-axons occurs when the projection is restored to its pre-lesion precision, and fails when it is not. We will use both confocal microscopy and immuno-EM analysis to test our hypothesis. Successful completion of the aims has implications for our understanding and treatment of human olfactory disease. Attempts to foster recovery in the clinical population require an understanding in depth of the inherent limits and capacities for regeneration. ? ?
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