Lrig1 and Wnt dependent niches dictate segregation of resident immune cells and melanocytes in murine tail epidermis

Abstract

The barrier-forming, self-renewing mammalian epidermis comprises keratinocytes, pigment-producing melanocytes, and resident immune cells as first-line host defense. In murine tail skin, interfollicular epidermis patterns into pigmented ′scale′ and non-pigmented ′interscale′ epidermis. Why and how mature melanocytes confine to scale epidermis is unresolved. Here, we delineate a cellular hierarchy among epidermal cell types that determines skin patterning. Already during postnatal development, melanocytes co-segregate with newly forming scale compartments. Intriguingly, this process coincides with partitioning of both Langerhans cells and dendritic epidermal T-cells to interscale epidermis, suggesting functional segregation of pigmentation and immune surveillance. Analysis of non-pigmented mice and of mice lacking melanocytes or resident immune cells revealed that immunocyte patterning is melanocyte- and melanin-independent, and, vice versa, immune cells do not control melanocyte localization. Instead, genetically enforced progressive scale fusion upon Lrig1 deletion showed that melanocytes and immune cells dynamically follow epithelial scale:interscale patterns. Importantly, disrupting Wnt-Lef1 function in keratinocytes caused melanocyte mislocalization to interscale epidermis, implicating canonical Wnt signaling in organizing the pigmentation pattern. Together, this work uncovered cellular and molecular principles underlying the compartmentalization of tissue functions in skin.