745 Regional expression of secreted WNT inhibitors dictates formation of hairless and poorly haired skin

Abstract

Different regions of mammalian skin vary in characteristics such as thickness, and hair follicle and sweat gland presence, size and density, that are reflected in differential responses to injury and disease. Positional information resides in the upper dermis but the responsible molecular mechanisms are poorly understood. To uncover these, we carried out comparative scRNA-seq of mouse embryonic dorsal, ear and plantar skin. This revealed differential regional expression of several secreted Wnt inhibitors, including Dkk2 and Sostdc1, suggesting regional modulation of Wnt signaling as an important mechanism controlling skin heterogeneity. In line with this, we showed previously that Dkk2-null mice develop regenerative hair follicles in normally hairless plantar skin. However, hair follicles in other regions had normal density and size. Loss of Sostdc1 is known to cause ectopic hair formation in nipple skin, extra vibrissae, and larger hair follicle placodes in trunk skin. We hypothesized that Dkk2 and Sostdc1 function partially redundantly to control additional regional skin features. To test this, we generated mice lacking both inhibitors. Double mutants displayed elevated Wnt signaling in embryonic plantar and ear skin, increased formation of plantar hair compared with Dkk2 single mutants, and growth of abnormally dense, long, thick hair on the external ears. Thus, regional modulation of Wnt signaling controls both the formation of hairless versus hairy skin, and the size and density of hair follicles in haired skin. These data support a new paradigm in which, rather than being dictated by an activating dermal signal as postulated in classical models, hair follicle formation is a default pathway that is actively suppressed by secreted inhibitors in skin regions that lack hair follicles or are poorly haired.