Vitamin D receptor is essential for normal keratinocyte stem cell function

The study demonstrated that transient activation of β-catenin signalling in adult mouse epidermis was sufficient to induce new hair follicles, as evidenced by the recruitment of resting hair follicles into the growth cycle and the formation of epithelial outgrowths expressing markers of hair follicle differentiation. This was achieved through the application of 4-hydroxytamoxifen (4OHT) to transgenic mice expressing a modified β-catenin. A single application of 4OHT was as effective as repeated doses. However, continuous activation of β-catenin was necessary to maintain hair follicle tumours, as these benign tumours regressed after the cessation of 4OHT treatment. The findings suggested that adult interfollicular epidermis and sebaceous glands could be reprogrammed, but sustained β-catenin signalling was crucial for maintaining the tumour state.

The study demonstrated that Tcf3 and Lef1 played crucial roles in regulating the differentiation of multipotent stem cells in the skin. Tcf3 acted independently of its β-catenin interacting domain to suppress epidermal differentiation and promote features of the follicle outer root sheath and multipotent stem cells, relying on its DNA binding and Groucho repressor-binding domains. In contrast, Lef1 required Wnt signaling and stabilized β-catenin to express hair-specific keratin genes and control hair differentiation. When lacking its β-catenin interacting domain, Lef1 (ΔNLef1) did not mimic Tcf3's effects but instead suppressed hair differentiation and promoted sebocyte differentiation. These findings highlighted the significant role of Tcf3/Lef complexes in determining cell fate lineages in skin stem cells.