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P63 regulates olfactory stem cell self-renewal and differentiation.

ABSTRACT: The olfactory epithelium is a sensory neuroepithelium that supports adult neurogenesis and tissue regeneration following injury, making it an excellent model for investigating neural stem cell regulation in vivo. Previous studies have identified the horizontal basal cell (HBC) as the neural stem cell of the postnatal olfactory epithelium. However, the molecules and pathways regulating HBC self-renewal and differentiation are unknown. In the present study, we demonstrate that the transcription factor p63, a member of the p53 tumor suppressor gene family known to regulate stem cell dynamics in other epithelia, is highly enriched in HBCs. We show that p63 is required cell autonomously for olfactory stem cell renewal and further demonstrate that p63 functions to repress HBC differentiation. These results provide critical insight into the genetic regulation of the olfactory stem cell in vivo and more generally provide an entrée toward understanding the coordination of stem cell self-renewal and differentiation.

SUBMITTER: Fletcher RB

PROVIDER: S-EPMC3240811 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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p63 regulates olfactory stem cell self-renewal and differentiation.

Fletcher Russell B RB Prasol Melanie S MS Estrada Jose J Baudhuin Ariane A Vranizan Karen K Choi Yoon Gi YG Ngai John J

Neuron 20111201 5

The olfactory epithelium is a sensory neuroepithelium that supports adult neurogenesis and tissue regeneration following injury, making it an excellent model for investigating neural stem cell regulation in vivo. Previous studies have identified the horizontal basal cell (HBC) as the neural stem cell of the postnatal olfactory epithelium. However, the molecules and pathways regulating HBC self-renewal and differentiation are unknown. In the present study, we demonstrate that the transcription fa ...[more]

PMID: 22153372

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Project description:BackgroundThe self-renewal of human pluripotent stem (hPS) cells including embryonic stem and induced pluripotent stem cells have been reported to be supported by various signal pathways. Among them, fibroblast growth factor-2 (FGF-2) appears indispensable to maintain self-renewal of hPS cells. However, downstream signaling of FGF-2 has not yet been clearly understood in hPS cells.Methodology/principal findingsIn this study, we screened a kinase inhibitor library using a high-throughput alkaline phosphatase (ALP) activity-based assay in a minimal growth factor-defined medium to understand FGF-2-related molecular mechanisms regulating self-renewal of hPS cells. We found that in the presence of FGF-2, an inhibitor of protein kinase C (PKC), GF109203X (GFX), increased ALP activity. GFX inhibited FGF-2-induced phosphorylation of glycogen synthase kinase-3β (GSK-3β), suggesting that FGF-2 induced PKC and then PKC inhibited the activity of GSK-3β. Addition of activin A increased phosphorylation of GSK-3β and extracellular signal-regulated kinase-1/2 (ERK-1/2) synergistically with FGF-2 whereas activin A alone did not. GFX negated differentiation of hPS cells induced by the PKC activator, phorbol 12-myristate 13-acetate whereas Gö6976, a selective inhibitor of PKCα, β, and γ isoforms could not counteract the effect of PMA. Intriguingly, functional gene analysis by RNA interference revealed that the phosphorylation of GSK-3β was reduced by siRNA of PKCδ, PKCε, and ζ, the phosphorylation of ERK-1/2 was reduced by siRNA of PKCε and ζ, and the phosphorylation of AKT was reduced by PKCε in hPS cells.Conclusions/significanceOur study suggested complicated cross-talk in hPS cells that FGF-2 induced the phosphorylation of phosphatidylinositol-3 kinase (PI3K)/AKT, mitogen-activated protein kinase/ERK-1/2 kinase (MEK), PKC/ERK-1/2 kinase, and PKC/GSK-3β. Addition of GFX with a MEK inhibitor, U0126, in the presence of FGF-2 and activin A provided a long-term stable undifferentiated state of hPS cells even though hPS cells were dissociated into single cells for passage. This study untangles the cross-talk between molecular mechanisms regulating self-renewal and differentiation of hPS cells.

Dataset Information

P63 regulates olfactory stem cell self-renewal and differentiation.

Publications

p63 regulates olfactory stem cell self-renewal and differentiation.

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