Fig. 5. TCF/LEF function in skin and hair. Structure and tissues of the mammalian hair follicle (A) and the differentiation pathways (black arrows) of multipotent stem cells in the skin (B). The stem cell niche (SC) resides in the bulge of the hair follicle and gives rise to the tissues of the epidermis of the skin (E), the sebaceous gland (SG), the outer-root sheath (ORS) the inner-root sheath (ORS) and the hair shaft (H). Larger rings in B represent cells, whereas the smaller rings within them represent their cell nuclei. The expression of TCF-3 and LEF-1 are indicated with the letter T or L, respectively, in the cell nuclei of cells. Note that LEF-1 is expressed in cells of the hair differentiation pathway, TCF-3 in the stem cells and the adjacent ORS, while the tissues of the skin (E and SG) are devoid of any TCF/LEF expression. The molecular activities of TCF-3 and LEF-1 are decisively different during hair and skin differentiation. Overexpression of full-length LEF-1 promotes hair differentiation (illustrated in B with green dotted arrow); whereas overexpression of full-length TCF-3 or constitutively repressing NTCF-3 prevents skin differentiation (E and SG, illustrated with red dotted inhibitory arrow) and promotes stem cell (SC) maintenance and differentiation into the adjacent ORS tissue (indicated with red dotted arrow). Overexpression of NLEF-1 interferes with hair differentiation by promoting trans-differentiation into cells that resemble those of the sebaceous gland (SG, indicated with red dotted arrow). TCF-3 therefore functions primarily as a repressor (indicated in red), while LEF-1 functions as an activator (indicated in green). Figure modified from Merrill et al. (Merrill et al., 2001).