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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 36; pp. E5068 - E5077
• Main Authors: Schnittke, Nikolai, Herrick, Daniel B., Lin, Brian, Peterson, Jesse, Coleman, Julie H., Packard, Adam I., Jang, Woochan, Schwob, James E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08.09.2015; National Acad Sciences
• Series: PNAS Plus
• Subjects: Animals; Biological Sciences; Blotting, Western; Cell Differentiation - genetics; Cell Proliferation - genetics; Male; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; Neurogenesis; Neurogenesis - genetics; Olfactory Mucosa - cytology; Olfactory Mucosa - metabolism; Olfactory Receptor Neurons - cytology; Olfactory Receptor Neurons - metabolism; Olfactory Receptor Neurons - transplantation; Phosphoproteins - genetics; Phosphoproteins - metabolism; PNAS Plus; Reverse Transcriptase Polymerase Chain Reaction; Sensory perception; Stem cells; Stem Cells - cytology; Stem Cells - metabolism; Tissues; Trans-Activators - genetics; Trans-Activators - metabolism; colony-forming unit; neural regeneration; lineage tracing; retroviral transduction; reserve stem cell
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1512272112

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.