EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling

• EdnrB signaling promotes proliferation and differentiation of melanocyte stem cells
• Wnt synergizes with EdnrB signaling to promote melanocyte regeneration
• Epithelial Edn1 rescues Mc1R loss in McSCs to regenerate epidermal melanocytes

SummaryDelineating the crosstalk between distinct signaling pathways is key to understanding the diverse and dynamic responses of adult stem cells during tissue regeneration. Here, we demonstrate that the Edn/EdnrB signaling pathway can interact with other signaling pathways to elicit distinct stem cell functions during tissue regeneration. EdnrB signaling promotes proliferation and differentiation of melanocyte stem cells (McSCs), dramatically enhancing the regeneration of hair and epidermal melanocytes. This effect is dependent upon active Wnt signaling that is initiated by Wnt ligand secretion from the hair follicle epithelial niche. Further, this Wnt-dependent EdnrB signaling can rescue the defects in melanocyte regeneration caused by Mc1R loss. This suggests that targeting Edn/EdnrB signaling in McSCs can be a therapeutic approach to promote photoprotective-melanocyte regeneration, which may be useful for those with increased risk of skin cancers due to Mc1R variants.

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