The circadian molecular clock creates epidermal stem cell heterogeneity

Janich, Peggy; Pascual, Gloria; Merlos-Suárez, Anna; Batlle, Eduard; Ripperger, Jürgen A.; Albrecht, Urs; Obrietan, Karl; Croce, Luciano Di; Benitah, Salvador Aznar

doi:10.1038/nature10649

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The circadian molecular clock creates epidermal stem cell heterogeneity

Janich, Peggy Center for Genomic Regulation and UPF, Barcelona, Spain
Pascual, Gloria Center for Genomic Regulation and UPF, Barcelona, Spain
Merlos-Suárez, Anna Institute for Research in Biomedicine, Barcelona, Spain
Batlle, Eduard Institute for Research in Biomedicine, Barcelona, Spain - Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
Ripperger, Jürgen A. University of Fribourg, Switzerland
Albrecht, Urs University of Fribourg, Switzerland
Obrietan, Karl Ohio State University, Columbus, USA
Croce, Luciano Di Center for Genomic Regulation and UPF, Barcelona, Spain - Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
Benitah, Salvador Aznar Center for Genomic Regulation and UPF, Barcelona, Spain - Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

09.11.2011

Published in:

Nature. - 2011, vol. 480, no. 7376, p. 209-214

English 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.

Faculty

Faculté des sciences et de médecine

Department

Département de Biologie

Language