Genomics of Olfactory Regeneration

The sensory neurons of the olfactory epithelium can be regenerated even if they are completely eliminated. This capacity lasts throughout the life of the animal and is of significant interest for both basic and applied neuroscience research. Its mechanisms are presumed to be relevant to the search for regenerationpromoting therapies for neurodegenerative disorders and trauma of the nervous system. Its mechanisms are also clearly relevant to neural development. To extend our understanding of olfactory regeneration, we have identified 1,205 mRNAs whose abundance within the olfactory epithelium changes after removal of the olfactory bulbs, a manipulation that causes the selective death and subsequent regeneration of the olfactory sensory neurons. Of these mRNAs, 303 increase contemporaneously with the proliferation of sensory neuron progenitors. The functions of the proteins encoded by these 303 mRNAs predict several underlying processes, including transcriptional activation of cell proliferation and differentiation, up-regulation of the cell cycle, axon outgrowth, and cell signaling. Only a handful of these proteins have previously been linked to olfactory regeneration or development. In this application, we propose to focus on a subset of gene products that are likely to be critical for proliferation and differentiation of the olfactory sensory neurons. The first specific aim is to define the capacity for each gene product to be involved in olfactory regeneration by determining which cell types express them, including spatial and temporal overlap with markers of known progenitor cell types. The second and third aims focus further on a subset of genes for which targeted deletions are available. These aims test whether the absence of the gene alters the development or regeneration of the olfactory epithelium, leading to changes at the cellular or molecular level. The proposed experiments will definitively test whether several proteins are dispensable for olfactory development and regeneration, and will define the potential roles of a couple dozen additional proteins.