Cui Chang-Yi, Durmowicz Meredith, Tanaka Tetsuya S, Hartung Andrew J, Tezuka Tadashi, Hashimoto Ken, Ko Minoru S H, Srivastava Anand K, Schlessinger David
Laboratory of Genetics, National Institutes of Health/National Institute on Aging, Baltimore, Maryland 21224, USA.
Hum Mol Genet. 2002 Jul 15;11(15):1763-73. doi: 10.1093/hmg/11.15.1763.
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-kappa B 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-kappa B pathway by EDA, and support its involvement in the regulation of the JNK pathway as well.
EDA基因突变会导致无汗性外胚层发育不良（EDA），伴有皮肤附属器形成缺陷。为了开始分析EDA通路，我们利用15000个基因的小鼠cDNA微阵列进行表达谱分析，比较野生型成年小鼠皮肤、EDA缺陷型（斑纹）小鼠以及补充了EDA-A1亚型的斑纹小鼠的皮肤，该亚型足以挽救多种斑纹表型。鉴于当前微阵列系统的灵敏度，估计有8500个基因（60%）表达，包括先前未在皮肤中鉴定出的转录因子和生长调节基因；但只有24个基因（0.16%）在野生型和斑纹型之间表现出显著差异，其中三分之一是新发现的基因。通过实时RT-PCR显示，15000个基因集中未包含的另外8个基因存在表达差异。在EDA-A1转基因斑纹小鼠中，32个受影响的基因中有16个显著恢复到野生型水平。在斑纹皮肤中观察到几种真皮基质基因显著上调，包括Col1a1、Col1a2、Col3a1和SPARC；相反，NEMO/NF-κB通路发生下调，该通路已与皮肤附属器形成有关，而第二条通路JNK/c-jun/c-fos及其靶基因的下调更为明显，该通路先前尚未与皮肤发育明确相关。这些数据与EDA对NF-κB通路的调节一致，并支持其也参与JNK通路的调节。
