Edar and Troy signalling pathways act redundantly to regulate initiation of hair follicle development
Edar and Troy signalling pathways act redundantly to regulate initiation of hair follicle development
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DOI：
10.1093/hmg/ddn232
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发表时间：
2008-11-01
影响因子：
3.5
通讯作者：
Mikkola, Marja L.
中科院分区：
文献类型：
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作者：
Pispa, Johanna;Pummila, Marja;Mikkola, Marja L.
外胚层器官的发育需要外胚层发育不良（Eda）（肿瘤坏死因子（TNF）家族成员）、其受体Edar和核因子κ B（NF-κ B）转录因子的下游活化的信号传导。在人类中，Eda途径组分的突变导致少汗性外胚层发育不良，这是一种以牙齿缺失、头发稀疏和汗腺缺陷为特征的综合征。据推测，EDA与另一个TNF途径冗余地调节外胚层器官发生。一个潜在的候选者是Troy（或TNFRSF 19或Taj），一种在其配体结合结构域中与Edar同源的TNF受体，并且以重叠模式表达。我们已经表征了Troy无效小鼠并将其与EDA缺陷小鼠杂交。单特洛伊突变体没有缺陷的外胚层器官。对双突变体的分析揭示了特洛伊在毛囊发育中的重要作用。在小鼠中，毛囊以三种不同的波发育。在Eda单突变体中只有初级毛囊缺失，而复合突变体也缺乏第二波毛囊，以及冠部中间的所有毛囊，导致局灶性脱发。用转基因报告构建体评估NF-κ B活性表明，Eda是发育中皮肤附件中NF-κ B信号传导的主要激活剂，并且令人惊讶地，Troy和Eda信号传导途径的功能重叠由NF-κ B独立途径介导。
The development of ectodermal organs requires signalling by ectodysplasin (Eda), a tumor necrosis factor (TNF) family member, its receptor Edar and downstream activation of the nuclear factor kappaB (NF-kappa B) transcription factor. In humans, mutations in the Eda pathway components cause hypohidrotic ectodermal dysplasia, a syndrome characterized by missing teeth, sparse hair and defects in sweat glands. It has been postulated that Eda acts redundantly with another TNF pathway to regulate ectodermal organogenesis. A potential candidate is Troy (or TNFRSF19 or Taj), a TNF receptor which is homologous with Edar in its ligand-binding domain, and is expressed in an overlapping pattern. We have characterized Troy null mice and crossed them with Eda-deficient mice. Single Troy mutants had no defects in ectodermal organs. Analysis of the double mutants revealed an essential role for Troy in hair follicle development. In mice, hair follicles develop in three different waves. Only primary hair follicles are missing in Eda single mutants, whereas the compound mutants lacked also the follicles of the second wave, as well as all hair follicles in the middle of crown leading to focal alopecia. Assessment of NF-kappa B activity with a transgenic reporter construct indicated that Eda is the main activator of NF-kappa B signalling in developing skin appendages and surprisingly that the functional overlap of Troy and Eda signalling pathways is mediated by NF-kappa B independent pathways.