Abstract
Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.
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Change history
07 December 2011
Author H.-Y.M.C. was added.
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Acknowledgements
We thank the AICR (Association for International Cancer Research), the Spanish Ministry of Health (FIS) and AGAUR (Agència de Gestió d'Ajuts Universitaris i de Recerca; Government of Cataluña) for financial support. P.J. is the recipient of an AGAUR PhD Fellowship, and G.P. of a FIS fellowship. We thank D. McMahon (Vanderbilt University) for providing us with the Per1–GFP mice; E. Wagner (CNIO) for the K5-SOS mice; B. Kübler, the FACS and Genomics units of the IRB (Institute de Recerca Biomedica), the CRG (Center for Genomic Regulation) core facilities and the Animal Unit (Juan Martin Caballero) for technical support.
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P.J. performed the experiments, and P.J. and S.A.B. analysed the results and wrote the manuscript. G.P. performed the analysis of K5-SOS mice, and A.M. and E.B. assisted P.J. in the initial FACS sorts. L.D.C. helped us with the initial ChIP experiments. K.O. provided the Per1–venus mice and H.-Y.M.C. generated the Per1–venus mice. J.R. and U.A. provided the Per1/Per2dKO mice.
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Supplementary information
Supplementary Information
This file contains Supplementary Figures 1-17 with legends and Supplementary Tables 2, 4 and 5 (see separate files for Supplementary Tables 1 and 3). (PDF 3030 kb)
Supplementary Table 1
This table contains affymetrix microarray data comparing Venusbright and Venusdim bulge cells of P19 Per1-Venus mice. (XLS 9142 kb)
Supplementary Table 3
This table contains affymetrix microarray data comparing basal epidermal cells of 10 months old Bmal1WT and Bmal1KO mice. (XLS 4179 kb)
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Janich, P., Pascual, G., Merlos-Suárez, A. et al. The circadian molecular clock creates epidermal stem cell heterogeneity. Nature 480, 209–214 (2011). https://doi.org/10.1038/nature10649
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DOI: https://doi.org/10.1038/nature10649