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 had earlier shown that the promoter region has transcription elements that include enhancers, possibly implicated in the tissue specificity of the gene; they include sites that implicate the Wnt pathway. ? We had also demonstrated that the Tabby mouse, which has many of the features observed in human EDA, is specifically mutated in the orthologous mouse gene. The gene was known to have 3 different classes of protein products (isoforms); we have now found additional isoforms for the functional A form. We have been investigating whether the different protein products function to help form different skin appendages, or whether they cooperate for all skin appendage formation. Various skin appendages are restored at least partially by a single isoform. We found that the same isoform has two kinds of effects in embryonic mice: determining the formation of certain appendages, including some types of hair follicles, and increasing the size of others, including sebaceous 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. Tests are planned to assess the capacity of a soluble, topical form of the isoform to prevent ocular surface disease and promote sweat gland formation in the Tabby mice. ? In additional studies to look at the final phases of hair follicle development, we are making a mouse model for the human disease Cartilage Hair Hypoplasia. The approaches to be used follow the model we have established for EDA, with expression profiling and careful phenotyping, including histology. These studies should facilitate attempts to maintain or reform hair follicles. ? To extend the analyses, we have done extensive microarray gene expression profiling for skin appendages at various times during their development. The studies thus far implicate a small number of genes that show significant quantitative changes in expression in Tabby compared to wild-type mouse skin. They include several major signal transduction pathways such as Wnt, SHH, and lymphotoxin in conjunction with NF-kB; and the changes are largely restored to normal levels in animals in which a transgene has restored much of the skin appendages. The lymphotoxin-beta pathway si newly defined as involved in skin appendage formation; and studies are continuing to detail thetime and mechanism of action of these pathways in the formation of sweat glands, hair follicles, and sebaceous glands.
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