Laurikkala Johanna, Pispa Johanna, Jung Han-Sung, Nieminen Pekka, Mikkola Marja, Wang Xiuping, Saarialho-Kere Ulpu, Galceran Juan, Grosschedl Rudolf, Thesleff Irma
Institute of Biotechnology, Viikki Biocenter, 00014 University of Helsinki, Finland.
Development. 2002 May;129(10):2541-53. doi: 10.1242/dev.129.10.2541.
X-linked and autosomal forms of anhidrotic ectodermal dysplasia syndromes (HED) are characterized by deficient development of several ectodermal organs, including hair, teeth and exocrine glands. The recent cloning of the genes that underlie these syndromes, ectodysplasin (ED1) and the ectodysplasin A receptor (EDAR), and their identification as a novel TNF ligand-receptor pair suggested a role for TNF signaling in embryonic morphogenesis. In the mouse, the genes of the spontaneous mutations Tabby (Ta) and downless (dl) were identified as homologs of ED1 and EDAR, respectively. To gain insight into the function of this signaling pathway in development of skin and hair follicles, we analyzed the expression and regulation of Eda and Edar in wild type as well as Tabby and Lef1 mutant mouse embryos. We show that Eda and Edar expression is confined to the ectoderm and occurs in a pattern that suggests a role of ectodysplasin/Edar signaling in the interactions between the ectodermal compartments and the formation and function of hair placodes. By using skin explant cultures, we further show that this signaling pathway is intimately associated with interactions between the epithelial and mesenchymal tissues. We also find that Ta mutants lack completely the placodes of the first developing tylotrich hairs, and that they do not show patterned expression of placodal genes, including Bmp4, Lef1, Shh, Ptch and Edar, and the genes for beta-catenin and activin A. Finally, we identified activin as a mesenchymal signal that stimulates Edar expression and WNT as a signal that induces Eda expression, suggesting a hierarchy of distinct signaling pathways in the development of skin and hair follicles. In conclusion, we suggest that Eda and Edar are associated with the onset of ectodermal patterning and that ectodysplasin/edar signaling also regulates the morphogenesis of hair follicles.
无汗性外胚层发育不良综合征（HED）的X连锁和常染色体形式的特征是包括毛发、牙齿和外分泌腺在内的几种外胚层器官发育缺陷。最近克隆了这些综合征的相关基因——外胚层发育不良蛋白（ED1）和外胚层发育不良蛋白A受体（EDAR），并将它们鉴定为一种新型肿瘤坏死因子（TNF）配体-受体对，这表明TNF信号传导在胚胎形态发生中起作用。在小鼠中，自发突变的Tabby（Ta）和downless（dl）基因分别被鉴定为ED1和EDAR的同源物。为了深入了解该信号通路在皮肤和毛囊发育中的功能，我们分析了野生型以及Tabby和Lef1突变小鼠胚胎中Eda和Edar的表达及调控情况。我们发现Eda和Edar的表达局限于外胚层，其表达模式表明外胚层发育不良蛋白/Edar信号传导在外胚层各部分之间的相互作用以及毛基板的形成和功能中发挥作用。通过使用皮肤外植体培养，我们进一步表明该信号通路与上皮组织和间充质组织之间的相互作用密切相关。我们还发现Ta突变体完全缺乏最早发育的触须毛的基板，并且它们没有显示出基板基因的模式化表达，包括Bmp4、Lef1、Shh、Ptch和Edar，以及β-连环蛋白和激活素A的基因。最后，我们确定激活素是一种刺激Edar表达的间充质信号，而WNT是一种诱导Eda表达的信号，这表明在皮肤和毛囊发育中存在不同信号通路的层次结构。总之，我们认为Eda和Edar与外胚层模式形成的起始有关，并且外胚层发育不良蛋白/edar信号传导也调节毛囊的形态发生。
