The peripheral olfactory system has a remarkable capacity for repair after injury, and the maintenance of that capacity depends on the persistence of neurocompetent stem cells. If the stem cells are destroyed, the injured tissue undergoes respiratory metaplasia, which is a major cause of sensory dysfunction in humans. Despite the importance attached to understanding the regulation of olfactory stem cells, there is much that is not yet known, starting with their identity. Work during the previous period of support demonstrated that among the population of globose basal cells (GBCs) are cells that have many of the characteristics of stem cells, including the potency to differentiate into all the constituent cell types and the existence of slowly cycling, label-retaining cells (a hallmark of stem cells in other tissues). The 3 Specific Aims proposed in this application will provide a more in depth understanding of olfactory stem cells and how they are regulated.
Aim 1 will use a transplantation/colony forming unit assay to determine the differentiate and generative capability of different marker-defined subsets of GBCs, including label-retaining ones.
Aim 2 will test whether expression of members of the bHLH transcription factor family signify (and might drive) irreversible commitment to a single lineage.
Aim 3 will test whether the Notch-Hes signal transduction pathway controls the choice point between neurons vs. non-neuronal cells that is made by the multipotent GBCs as they differentiate. Successful completion of the Aims will advance our understanding of olfactory stem cells and hasten their potential use as a therapeutic modality.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Davis, Barry
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Tufts University
Anatomy/Cell Biology
Schools of Medicine
United States
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Herrick, Daniel B; Guo, Zhen; Jang, Woochan et al. (2018) Canonical Notch Signaling Directs the Fate of Differentiating Neurocompetent Progenitors in the Mammalian Olfactory Epithelium. J Neurosci 38:5022-5037
Lin, Brian; Coleman, Julie H; Peterson, Jesse N et al. (2017) Injury Induces Endogenous Reprogramming and Dedifferentiation of Neuronal Progenitors to Multipotency. Cell Stem Cell 21:761-774.e5
Schwob, James E; Jang, Woochan; Holbrook, Eric H et al. (2017) Stem and progenitor cells of the mammalian olfactory epithelium: Taking poietic license. J Comp Neurol 525:1034-1054
Peterson, Jesse N; Lin, Brian; Shin, Jong et al. (2017) Replication of JC Virus DNA in the G144 Oligodendrocyte Cell Line Is Dependent Upon Akt. J Virol 91:
Vyas, Rutesh N; Meredith, Diane; Lane, Robert P (2017) Lysine-specific demethylase-1 (LSD1) depletion disrupts monogenic and monoallelic odorant receptor (OR) expression in an olfactory neuronal cell line. Mol Cell Neurosci 82:1-11
Coleman, Julie H; Lin, Brian; Schwob, James E (2017) Dissecting LSD1-Dependent Neuronal Maturation in the Olfactory Epithelium. J Comp Neurol 525:3391-3413
Herrick, Daniel B; Lin, Brian; Peterson, Jesse et al. (2017) Notch1 maintains dormancy of olfactory horizontal basal cells, a reserve neural stem cell. Proc Natl Acad Sci U S A 114:E5589-E5598
Packard, Adam I; Lin, Brian; Schwob, James E (2016) Sox2 and Pax6 Play Counteracting Roles in Regulating Neurogenesis within the Murine Olfactory Epithelium. PLoS One 11:e0155167
Kilinc, Seda; Savarino, Alyssa; Coleman, Julie H et al. (2016) Lysine-specific demethylase-1 (LSD1) is compartmentalized at nuclear chromocenters in early post-mitotic cells of the olfactory sensory neuronal lineage. Mol Cell Neurosci 74:58-70
Schnittke, Nikolai; Herrick, Daniel B; Lin, Brian et al. (2015) Transcription factor p63 controls the reserve status but not the stemness of horizontal basal cells in the olfactory epithelium. Proc Natl Acad Sci U S A 112:E5068-77

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