The regulation of melanocyte stem cells by Wnt signaling

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Summary Our long-term goal is to understand the precise location and molecular regulation of melanocyte stem cells (McSCs), with a special emphasis on the role(s) of the Wnt pathway in regulating normal and abnormal McSCs. Our previous studies reported that McSCs within the hair follicle (HF McSCs) can contribute to hair pigmentation and possess the potential to produce epidermal melanocytes through activation of Wnt signaling. More recently, we reported that oncogenic HF McSCs can transform into melanoma and demonstrated that Wnt signaling crosstalks with mechanisms elicited by oncogenic mutations to drive melanomagenesis. Nonetheless, an epidermal source of McSCs has been commonly proposed as the most likely contributor to skin MCs, skin pigmentation and the majority of pigmentation disorders, including vitiligo, post-inflammatory hyperpigmentation, and the deadly skin cancer melanoma, disorders that arise from interfollicular skin epidermis in humans. Thus, during the last funding period, we asked a fundamental question “do McSCs also exist within the skin epidermis?” Addressing this requires the examination of epidermal melanocytes for their self-sustainability and regenerative capacities without contamination of HF McSCs, which possess the potential to give rise to MCs, at least after skin wounding. The major challenge in the field has been the lack of a melanocyte-specific tool to distinguish epidermal McSCs (epMcSCs) from HF McSCs in normal skin where numerous hair follicles are present. Here, we have created a novel mouse model, OCA2-creERT, that solely targets pigmented epidermal melanocytes without targeting HF McSCs. We have used this novel tool to demonstrate that OCA2+ epidermal melanocytes are pigmented, yet self-sustaining, and possess the ability to regenerate during homeostasis and proliferate and differentiate following physiological stimuli like UVB irradiation. These findings have led us to hypothesize that Oca2+ MCs possess characteristics of stem cell/progenitor cells and perform regenerative functions in the skin independent of HF McSCs. This new model provides us with the necessary tools to address, in the next granting period, how Oca2+ MCs possess the lineage capacity to regenerate various skin melanocytes while retaining a self-renewing capacity long-term (Aim1), how the Wnt signaling pathway regulates their regenerative behavior in collaboration with other key signaling pathways (Aim2) and whether OCA2+ epidermal melanocytes can be a cellular source for nevi with a potential for melanoma transformation under the influence of Wnt signaling (Aim3).