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 the disorder encodes a protein, which we have named ectodysplasin-A, has a single transmembrane region with collagenous and TNF-receptor segments in a long extracellular 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 and EGF pathways. We had also demonstrated that the Tabby mouse, which has many of the features observed in human EDA, has lost the function of the orthologous mouse gene. The gene has 3 different classes of protein products. Several groups have shown that particular protein species bind to different cellular receptors to affect the control of gene expression by a transcription control system (NF-kappaB). We have now begun to ask whether the different protein products function to help form different skin appendages, or whether they cooperate for all skin appendage formation. To distinguish among these alternatives, we put one of the isoforms of the gene back into a Tabby animal. The result is unequivocal: all skin appendages are restored at least partially. We are now beginning to look at Tabby animals transgenic for other of the protein products (isoforms), or for combinations of isoforms, turning their formation on or off at defined times during fetal development in the mice by using a controllable promoter. These experiments should determine the relative contribution of different isoforms to the formation and maintenance of the appendages. We have also begun extensive microarray analyses of gene expression in these animals. 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; the changes are largely restored to normal levels in the transgenic animals. Extensions of the promoter studies are designed to analyze steps leading to ectodysplasin formation, and the combination of histology, phenotyping, and gene expression assays in the transgenic animals are providing information about its action.
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