Human Molecular Genetics, 2002, Vol. 11, No. 15 1763-1773
© 2002 Oxford University Press
EDA targets revealed by skin gene expression profiles of wild-type, Tabby and Tabby EDA-A1 transgenic mice
1Laboratory of Genetics, NIH/National Institute on Aging, Baltimore, Maryland 21224, USA, 2J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina 29646, USA, 3Department of Dermatology, Kinki University School of Medicine, Osaka 589, Japan and 4Department of Dermatology and Syphilology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
Received April 10, 2002; Accepted May 24, 2002
Mutations in the EDA gene cause anhidrotic ectodermal dysplasia (EDA), with lesions in skin appendage formation. To begin to analyze EDA pathways, we have used expression profiling on 15 000-gene mouse cDNA microarrays, comparing adult mouse skin from wild-type, EDA-defective (Tabby) mice, and Tabby mice supplemented with the EDA-A1 isoform, which is sufficient to rescue multiple Tabby phenotypes. Given the sensitivity of the current microarray system, 8500 genes (60%) were estimated to be expressed, including transcription factors and growth-regulatory genes that had not previously been identified in skin; but only 24 (0.16%), one-third of them novel, showed significant differences between wild type and Tabby. An additional eight genes not included in the 15 000 gene set were shown to have expression differences by real-time RT–PCR. Sixteen of 32 affected genes were restored significantly toward wild-type levels in EDA-A1 transgenic Tabby mice. Significant up-regulation in Tabby skin was observed for several dermal matrix genes, including Col1a1, Col1a2, Col3a1 and Sparc. In contrast, down-regulation occurred for the NEMO/NF-kB pathway, already implicated in skin appendage formation, and even more markedly for a second pathway, JNK/c-jun/c-fos and their target genes, that has not previously been clearly associated with skin development. These data are consistent with the regulation of the NF-kB pathway by EDA, and support its involvement in the regulation of the JNK pathway as well.
* To whom correspondence should be addressed. Tel: +1 4105588337; Fax: +1 4105588331; Email: SchlessingerD{at}grc.nia.nih.gov
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