Merkel cells detect gentle touch and localize to epithelial touch dome structures in skin. Merkel cells display similarities to Merkel cell carcinoma, an aggressive and often fatal cancer that predominantly occurs in elderly and sun-exposed skin, and Merkel cell progenitors are a possible cell of origin for this devastating disease. In adult life, Merkel cells are regenerated from K17+ touch dome cells, but the mechanisms controlling this process are unclear. We found that nuclear b-catenin and Wnt reporter expression localize to K17+ touch dome cells in adult mouse skin. To determine whether Wnt/b-catenin signaling marks self-renewing stem/progenitor cells in the touch dome, we used mice in which tamoxifen-inducible Cre recombinase was knocked into the locus for Axin2, a direct Wnt target gene, in combination with fluorescent Cre reporters that permit lineage tracing of Axin2+ cells. These experiments identified self-renewing Wnt-active touch dome progenitors that were maintained over natural regeneration and gave rise to K8+ Merkel cells. To determine whether Wnt/b-catenin signaling is required for Merkel cell renewal, we induced expression of the Wnt/b-catenin inhibitor Dkk1 or deletion of epithelial b-catenin in adult mouse epidermis. Either of these manipulations caused gradual depletion of K8+ Merkel cells without affecting touch dome maintenance. Mice lacking the Wnt ligand Wnt10a developed hair follicles, but displayed delayed anagen onset in adult skin. Merkel cells and touch domes were present in Wnt10a-/mice at early postnatal stages. However, with age, K8+ Merkel cells, but not K17+ touch dome cells, were gradually lost from Wnt10a mutant skin. Our data identify Wnt-active selfrenewing stem cells in touch domes and demonstrate that WNT10A/b-catenin signaling is required for Merkel cell renewal in adult life.
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