Correction: Joiner and Green et al., “Primary Cilia on Horizontal Basal Cells Regulate Regeneration of the Olfactory Epithelium”

Adult neural stem cells/progenitor cells residing in the basal layer of the olfactory epithelium are capable of reconstituting the neuroepithelium even after severe damage. The molecular events underlying this regenerative capacity remain elusive. Here we show that the repair of neuroepithelium after lesioning is accompanied by an acute, but self-limited, inflammatory process. Attenuation of inflammatory cell recruitment and cytokine production by dexamethasone impairs proliferation of progenitor horizontal basal cells (HBCs) and subsequent neuronal differentiation. Using TNF-α receptor-deficient mice, we identify TNF-α signaling as an important contributor to this inflammatory and reparative process, mainly through TNF-α receptor 1. HBC-selective genetic ablation of RelA (p65), the transcriptional activator of the NF-κB pathway, retards inflammation and impedes proliferation at the early stages of regeneration and suggests HBCs directly participate in cross-talk between immune response and neurogenesis. Loss of RelA in the regenerating neuroepithelium perturbs the homeostasis between proliferation and apoptosis while enhancing JNK signaling. Together, our results support a model in which acute inflammation after injury initiates important regenerative signals in part through NF-κB–mediated signaling that activates neural stem cells to reconstitute the olfactory epithelium.

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Transcription factor p63 controls the reserve status but not the stemness of horizontal basal cells in the olfactory epithelium

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1512272112 ◽

2015 ◽

Vol 112 (36) ◽

pp. E5068-E5077 ◽

Cited By ~ 37

Author(s):

Nikolai Schnittke ◽

Daniel B. Herrick ◽

Brian Lin ◽

Jesse Peterson ◽

Julie H. Coleman ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Olfactory Epithelium ◽

Tissue Injury ◽

Cell Types ◽

Stem Cell Population ◽

Basal Cells ◽

Loss Of Function ◽

Down Regulation ◽

Horizontal Basal Cells

Adult tissue stem cells can serve two broad functions: to participate actively in the maintenance and regeneration of a tissue or to wait in reserve and participate only when activated from a dormant state. The adult olfactory epithelium, a site for ongoing, life-long, robust neurogenesis, contains both of these functional stem cell types. Globose basal cells (GBCs) act as the active stem cell population and can give rise to all the differentiated cells found in the normal tissue. Horizontal basal cells (HBCs) act as reserve stem cells and remain dormant unless activated by tissue injury. Here we show that HBC activation following injury by the olfactotoxic gas methyl bromide is coincident with the down-regulation of protein 63 (p63) but anticipates HBC proliferation. Gain- and loss-of-function studies show that this down-regulation of p63 is necessary and sufficient for HBC activation. Moreover, activated HBCs give rise to GBCs that persist for months and continue to act as bona fide stem cells by participating in tissue maintenance and regeneration over the long term. Our analysis provides mechanistic insight into the dynamics between tissue stem cell subtypes and demonstrates that p63 regulates the reserve state but not the stem cell status of HBCs.

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Neural crest-derived horizontal basal cells as tissue stem cells in the adult olfactory epithelium

Neuroscience Research ◽

10.1016/j.neures.2012.11.005 ◽

2013 ◽

Vol 75 (2) ◽

pp. 112-120 ◽

Cited By ~ 40

Author(s):

Jun Suzuki ◽

Kaichi Yoshizaki ◽

Toshimitsu Kobayashi ◽

Noriko Osumi

Keyword(s):

Stem Cells ◽

Neural Crest ◽

Olfactory Epithelium ◽

Basal Cells ◽

Horizontal Basal Cells

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An immunochemical, ultrastructural, and developmental characterization of the horizontal basal cells of rat olfactory epithelium

The Journal of Comparative Neurology ◽

10.1002/cne.903630111 ◽

1995 ◽

Vol 363 (1) ◽

pp. 129-146 ◽

Cited By ~ 123

Author(s):

Eric H. Holbrook ◽

Karen E. Mieleszko Szumowski ◽

James E. Schwob

Keyword(s):

Olfactory Epithelium ◽

Basal Cells ◽

Horizontal Basal Cells

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Zone-specific damage of the olfactory epithelium under protein restriction

Scientific Reports ◽

10.1038/s41598-020-79249-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Ayinuer Tuerdi ◽

Shu Kikuta ◽

Makoto Kinoshita ◽

Teru Kamogashira ◽

Kenji Kondo ◽

...

Keyword(s):

Oxidative Stress ◽

Olfactory Epithelium ◽

Control Diet ◽

Intervention Strategy ◽

Protein Restriction ◽

Outer Hair Cells ◽

Basal Cells ◽

Cell Dynamics ◽

Age Related ◽

Positive Effect

AbstractOxidative stress causes tissue damage, affecting age-related pathologies. Protein restriction (PR) provides a powerful intervention strategy for reducing oxidative stress, which may have a positive effect on individual organs. However, it is unknown whether PR intervention influences the olfactory system. Here, we investigated how 10 months of PR could affect the cell dynamics of the olfactory epithelium (OE) in mice. We found that PR reduced age-related loss of outer hair cells in the cochlea, providing preventive effects against age-related hearing loss. In contrast, PR resulted in reduced mature olfactory sensory neurons (OSNs), increased proliferative basal cells, and increased apoptotic OSNs in zone 1 (the only area containing neurons expressing NQO1 [quinone dehydrogenase 1]) of the OE in comparison with animals given a control diet. Substantial oxidative stress occurred in NQO1-positive cells and induced apoptotic OSNs in zone 1. These results indicate that in contrast to the positive effect on the auditory system, PR induces oxidative stress and structurally and functionally negative effects on OSNs in zone 1, which is probably involved in the bioactivation of NQO1.

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Multipotency of purified, transplanted globose basal cells in olfactory epithelium

The Journal of Comparative Neurology ◽

10.1002/cne.11031 ◽

2004 ◽

Vol 469 (4) ◽

pp. 457-474 ◽

Cited By ~ 111

Author(s):

Xueyan Chen ◽

Hengsheng Fang ◽

James E. Schwob

Keyword(s):

Olfactory Epithelium ◽

Basal Cells

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Differential and overlapping expression patterns of X-dll3 and Pax-6 genes suggest distinct roles in olfactory system development of the African clawed frog Xenopus laevis

Journal of Experimental Biology ◽

10.1242/jeb.204.12.2049 ◽

2001 ◽

Vol 204 (12) ◽

pp. 2049-2061 ◽

Cited By ~ 1

Author(s):

Marie-Dominique Franco ◽

Michael P. Pape ◽

Jennifer J. Swiergiel ◽

Gail D. Burd

Keyword(s):

Xenopus Laevis ◽

Expression Pattern ◽

Olfactory Epithelium ◽

Olfactory System ◽

De Novo ◽

System Development ◽

Expression Patterns ◽

Basal Cells ◽

Olfactory Placode ◽

Water Borne

SUMMARY In Xenopus laevis, the formation of the adult olfactory epithelium involves embryonic, larval and metamorphic phases. The olfactory epithelium in the principal cavity (PC) develops during embryogenesis from the olfactory placode and is thought to respond to water-borne odorants throughout larval life. During metamorphosis, the PC undergoes major transformations and is exposed to air-borne odorants. Also during metamorphosis, the middle cavity (MC) develops de novo. The olfactory epithelium in the MC has the same characteristics as that in the larval PC and is thought to respond to water-borne odorants. Using in situ hybridization, we analyzed the expression pattern of the homeobox genes X-dll3 and Pax-6 within the developing olfactory system. Early in development, X-dll3 is expressed in both the neuronal and non-neuronal ectoderm of the sense plate and in all cell layers of the olfactory placode and larval PC. Expression becomes restricted to the neurons and basal cells of the PC by mid-metamorphosis. During metamorphosis, X-dll3 is also expressed throughout the developing MC epithelium and becomes restricted to neurons and basal cells at metamorphic climax. This expression pattern suggests that X-dll3 is first involved in the patterning and genesis of all cells forming the olfactory tissue and is then involved in neurogenesis or neuronal maturation in putative water- and air-sensing epithelia. In contrast, Pax-6 expression is restricted to the olfactory placode, larval PC and metamorphic MC, suggesting that Pax-6 is specifically involved in the formation of water-sensing epithelium. The expression patterns suggest that X-dll3 and Pax-6 are both involved in establishing the olfactory placode during embryonic development, but subtle differences in cellular and temporal expression patterns suggest that these genes have distinct functions.

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