Developmental Biology Program, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
J Invest Dermatol. 2012 Apr;132(4):1094-102. doi: 10.1038/jid.2011.453. Epub 2012 Jan 26.
Ectodysplasin (Eda), a member of the tumor necrosis factor (Tnf) family, regulates skin appendage morphogenesis via its receptor Edar and transcription factor NF-κB. In humans, inactivating mutations in the Eda pathway components lead to hypohidrotic ectodermal dysplasia (HED), a syndrome characterized by sparse hair, tooth abnormalities, and defects in several cutaneous glands. A corresponding phenotype is observed in Eda-null mice, where failure in the initiation of the first wave of hair follicle development is a hallmark of HED pathogenesis. In an attempt to discover immediate target genes of the Eda/NF-κB pathway, we performed microarray profiling of genes differentially expressed in embryonic skin explants after a short exposure to recombinant Fc-Eda protein. Upregulated genes included components of the Wnt, fibroblast growth factor, transforming growth factor-β, Tnf, and epidermal growth factor families, indicating that Eda modulates multiple signaling pathways implicated in skin appendage development. Surprisingly, we identified two ligands of the chemokine receptor cxcR3, cxcl10 and cxcl11, as new hair-specific transcriptional targets of Eda. Deficiency in cxcR3 resulted in decreased primary hair follicle density but otherwise normal hair development, indicating that chemokine signaling influences the patterning of primary hair placodes only.
外胚层发育不全素（Eda）是肿瘤坏死因子（TNF）家族的一员，通过其受体 Edar 和转录因子 NF-κB 调节皮肤附属物形态发生。在人类中，Eda 通路成分的失活突变导致少汗性外胚层发育不全（HED），其特征是毛发稀疏、牙齿异常和几种皮肤腺体缺陷。在 Eda 缺失的小鼠中观察到相应的表型，其中毛囊发育的第一波启动失败是 HED 发病机制的标志。为了发现 Eda/NF-κB 通路的直接靶基因，我们对短时间暴露于重组 Fc-Eda 蛋白后的胚胎皮肤外植体中差异表达的基因进行了微阵列分析。上调的基因包括 Wnt、成纤维细胞生长因子、转化生长因子-β、TNF 和表皮生长因子家族的成分，表明 Eda 调节多个与皮肤附属物发育有关的信号通路。令人惊讶的是，我们鉴定出趋化因子受体 cxcR3 的两个配体 cxcl10 和 cxcl11，作为 Eda 的新毛发特异性转录靶标。cxcR3 缺陷导致初级毛囊密度降低，但其他毛发发育正常，表明趋化因子信号仅影响初级毛囊基板的模式形成。
