Abnormalities of stem cell function and/or the destruction of stem cells leads to an olfactory epithelium (OE) that remains olfactory (including a full complement of sustentacular cells), but one that has no neurons, no globose basal cells, and no ongoing neurogenesis. Horizontal basal cells (HBCs) are still evident in aneuronal OE, but clearly are not functioning as multipotent progenitors/stem cells as they can and do under other circumstances. These and other data indicate that HBCs must be activated in some way by signals emanating from a damaged epithelium, in order to function as stem cells. Recently, we have shown that the transcription factor p63 is key to HBC differentiation and regeneration. We will test whether p63 is the key factor that regulates (prevents) HBC activation using a mouse genetic approach.
In Aim 1 we will conditionally knock-out and conditionally over-express p63 selectively in HBCs, using K5 driver lines, and analyze clonal progeny from the targeted HBCs. Signaling via the Wnt and Notch pathways play antagonistic roles in regulating stem cells and their transition to more differentiated and shorter-lived progenitors. Moreover, both of them interface with p63 in that regulation. Accordingly, in Aims 2 and 3, we will assess how knock-out vs. constitutive activation of the Notch and Wnt pathways, respectively, affect HBC activation and function as progenitor. We will use the same kind of approach to achieve cell type- and temporal-control over the targeted genes. We expect that the results will show that p63 is the master regulator of HBC activation and that both Wnt and Notch pathways will participate in controlling both p63 and HBC activation. After completion of the experiments, we will be poised to apply small molecule inhibitors of p63 and the key signaling pathways to the problem of restoring neurogenesis to an aneuronal OE.
Olfactory dysfunction is a nearly universal consequence of aging and has serious consequences on nutritional status as well as quality of life more generally. In some cases, exhaustion and/or inappropriately prolonged dormancy of the stem cells of the olfactory epithelium looks to be the culprit. The experiments proposed in this grant test how olfactory stem cells can be awakened in mice so that the epithelium is restored to health. We will manipulate a key transcription factor, p63, that acts as the master switch for one category of olfactory stem cells, as well as the Notch and Wnt pathways that act on p63. When completed, we can use the information gained to design potential therapeutic approaches to reinvigorate stem cells.
|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|
|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|
|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|
|Gilbert, M A; Lin, B; Peterson, J et al. (2015) Neuregulin1 and ErbB expression in the uninjured and regenerating olfactory mucosa. Gene Expr Patterns 19:108-19|
|Jang, Woochan; Chen, Xueyan; Flis, Daniel et al. (2014) Label-retaining, quiescent globose basal cells are found in the olfactory epithelium. J Comp Neurol 522:731-49|
|Xie, Fang; Fang, Cheng; Schnittke, Nikolai et al. (2013) Mechanisms of permanent loss of olfactory receptor neurons induced by the herbicide 2,6-dichlorobenzonitrile: effects on stem cells and noninvolvement of acute induction of the inflammatory cytokine IL-6. Toxicol Appl Pharmacol 272:598-607|
|Krolewski, Richard C; Packard, Adam; Schwob, James E (2013) Global expression profiling of globose basal cells and neurogenic progression within the olfactory epithelium. J Comp Neurol 521:833-59|
|Peluso, Carolyn E; Jang, Woochan; Drager, Ursula C et al. (2012) Differential expression of components of the retinoic acid signaling pathway in the adult mouse olfactory epithelium. J Comp Neurol 520:3707-26|
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