X-linked anhidrotic ectodermal dysplasia (EDA) is the most frequently occurring of more than 175 ectodermal dysplasias affecting one or more skin appendages. The gene that is mutated to cause this disorder encodes a protein, which we have named ectodysplasin-A, has a single transmembrane region with collagenous and TNF-ligand segments in a long extracelliular carboxyterminal tail. Because individuals with EDA have sparse hair, rudimentary teeth, and few sweat glands, the gene is likely involved at an early point in development. We demonstrated that the Tabby mouse, which has many of the features observed in human EDA, is specifically mutated in the corresponding mouse gene. We found that provision of DNA encoding a variant of ectodysplasin in embryonic mice rstores hair follicles and sweat glands. We also have characterized eye phenotypes of Tabby mice including blindness and inflammation susceptibility, and they are also reversed by supplementation with the same isoform. In additional studies to look at the final phases of hair follicle development, we are studying the human disease Cartilage Hair Hypoplasia in a mouse model. These studies should facilitate attempts to maintain or reform hair follicles. In mechanistic studies, we have shown that EDA acts through the powerful NF-kB signaling pathway to activate four major target pathways, including the unanticipated involvement of lymphotoxin-beta, a molecule previously only known to help form immune system organs. EDA and all of the downstream pathways are required to continue the development of already initiated skin appendages. Work is continuing to analyze the process and its regulation in detail in mouse models. The models include the study of mice bearing skin-specific transgenes encoding Dkk4, which appears to regulate EdA expression; Shh, which is a major target of EDA; Nemo, a bridge to the NF-kB pathway; and Troy, a possible receptor for EDA action.