Role of the Wnt/beta-catenin signaling pathway in the regulation of melanocyte stem cells

Melanocyte stem cells (McSCs) are one of the constituents of the highly regenerative mammalian hair follicle. These slow-cycling and self-renewing stem cells are located in the bulge and secondary hair germ (sHG) of the follicle. During hair regrowth, McSCs generate mature progeny that produce pigment for incorporation into growing hair and consequently, unpigmented hair serves as a convenient reporter for inconsistent behavior in McSCs. Previous studies showed that Wnt/beta-catenin signaling specifies the melanocyte lineage from neural crest cells. However, the role of this pathway in post-natal melanocytes in skin was unknown. We used different physiological models to examine regulation of McSCs by Wnt/beta-catenin signaling.;We identified beta-catenin activation in sHG McSCs at the onset of hair follicle regeneration. Using genetic mouse models that specifically target McSCs, we showed that Wnt activation in McSCs drives their differentiation into pigment-producing melanocytes. Conversely, a lack of beta-catenin in McSCs led to hair graying in mice. Downregulation of Wnt is necessary to maintain the McSCs in their undifferentiated status. During follicular morphogenesis, we found similar suppression of Wnt signaling in melanocyte precursors that locate to the presumptive bulge formed by epithelial cells and generate McSCs. Upon wounding, Wnt/beta-catenin activation is required for proper generation and expansion of differentiated melanocytes in the wound area. The data define a novel role for Wnt/beta-catenin signaling in the regulation of McSCs and can serve as an important basis for development of therapies for pigmentation disorders.