An effector of intercellular adhesion, beta-catenin also functions in Wnt signaling, associating with Lef-1/Tcf DNA-binding proteins to form a transcription factor. We report that this pathway operates in keratinocytes and that mice expressing a stabilized beta-catenin controlled by an epidermal promoter undergo a process resembling de novo hair morphogenesis. The new follicles formed sebaceous glands and dermal papilla, normally established only in embryogenesis. As in embryologically initiated hair germs, transgenic follicles induce Lef-1, but follicles are disoriented and defective in sonic hedgehog polarization. Additionally, proliferation continues unchecked, resulting in two types of tumors also found in humans. Our findings suggest that transient beta-catenin stabilization may be a key player in the long-sought epidermal signal leading to hair development and implicate aberrant beta-catenin activation in hair tumors.

Gene knockout technology has provided a powerful tool for functional analyses of genes expressed preferentially in a particular tissue. Given marked similarities between human and mouse skin, such studies with epidermally expressed genes have often provided valuable insights into human genetic skin disorders. Efficient silencing of a specified gene in a temporally regulated and epidermal-specific fashion could extend functional analyses to broadly expressed genes and increase the categories of human skin disorders to which parallels could be drawn. We have generated transgenic mice expressing Cre and a fusion protein between Cre recombinase and the tamoxifen responsive hormone-binding domain of the estrogen receptor (CreER tam ) under the control of the human keratin 14 (K14) promoter. This promoter is strongly active in dividing cells of epidermis and some other stratified squamous epithelia. With K14-Cre, transgenic embryos recombine genetically introduced loxP sequences efficiently and selectively in the genomes of keratinocytes that reside in embryonic day 14.5 skin, tongue, and esophagus. With K14-CreER tam , postnatal transgenic mice show no Cre activity until tamoxifen is administered. If orally administered, tamoxifen activates keratinocyte-specific CreER tam , allowing recombination of loxP sequences in epidermis, tongue, and esophagus. If topically administered, tamoxifen allows recombination in the area of skin where tamoxifen was applied. Finally, we show that epidermal cells harboring a Cre-dependent rearranged genome persist for many months after tamoxifen application, indicating that the epidermal stem cell population has been targeted efficiently. These tools now pave the way for testing the functional role of different somatic mutations that may exist in mosaic disorders of the skin, including squamous and basal cell carcinomas.

BPAG1 is the major antigenic determinant of autoimmune sera of bullous pemphigoid (BP) patients. It is made by stratified squamous epithelia, where it localizes to the inner surface of specialized integrin-mediated adherens junctions (hemidesmosomes). To explore the function of BPAG1 and its relation to BP, we targeted the removal of the BPAG1 gene in mice. Hemidesmosomes are otherwise normal, but they lack the inner plate and have no cytoskeleton attached. Though not affecting cell growth or substratum adhesion, this compromises mechanical integrity and influences migration. Unexpectedly, the mice also develop severe dystonia and sensory nerve degeneration typical of dystonia musculorum (dt/dt) mice. We show that in at least one other strain of dt/dt mice, BPAG1 gene is defective.