Ectodysplasin regulates the lymphotoxin-β pathway for hair differentiation
Ectodysplasin regulates the lymphotoxin-β pathway for hair differentiation
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DOI：
10.1073/pnas.0509678103
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发表时间：
2006-06-13
影响因子：
11.1
通讯作者：
Schiessinger, David
中科院分区：
文献类型：
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作者：
Cui, Chang-Yi;Hashimoto, Tsuyoshi;Schiessinger, David
EDA基因突变导致无汗/少汗性外胚层发育不良，这是一种以人类和小鼠模型“虎斑猫”（Ta）中毛发、汗腺和牙齿形成缺陷为特征的疾病。该基因编码外胚层发育不良，一种激活NF-κ B信号通路的TNF配体家族成员，但下游靶点和皮肤附件形成的机制仅得到部分分析。WT和Ta小鼠毛囊发育期间胚胎皮肤的比较转录谱确定了四种途径中的关键无汗/少汗外胚层发育不良（EDA）效应子，其中三种已经涉及毛囊形成。它们包括Shh及其效应物，以及Wnt（Dkk 4）和BMP（Sostdc 1）通路的拮抗剂。第四种途径是出乎意料的，是一种基于光敏素β（LT β）/ReIB的变体NF-κ B信号级联。以前只知道参与淋巴器官发生，LT β是丰富的发展中的毛囊WT，但不是在Ta小鼠。此外，在缺乏LT β的小鼠中，所有三种类型的小鼠毛发仍然形成，但结构都异常。保卫毛变得波浪形和不规则，锯齿形/auchen毛失去了他们的扭结，并在Ta动物的特征表型，锥毛的数量增加了一倍，是典型的扭曲和捏。接受WT骨髓移植的LT β缺失小鼠保持突变的毛发表型，与独立于其在淋巴细胞中的表达的皮肤中的自主LT β作用一致。因此，作为EDA靶点，LT β调节发育中毛囊的毛发形式;当EDA有缺陷时，LT β活化的失败可以解释Ta表型的一部分。
Mutations in the EDA gene cause anhidrotic/hypohidrotic ectodermal dysplasia, a disorder characterized by defective formation of hair, sweat glands, and teeth in humans and in a mouse model, "Tabby" (Ta). The gene encodes ectodysplasin, a TNF ligand family member that activates the NF-kappa B-signaling pathway, but downstream targets and the mechanism of skin appendage formation have been only partially analyzed. Comparative transcription profiling of embryonic skin during hair follicle development in WT and Ta mice identified critical anhidrotic/hypohidrotic ectodermal dysplasia (EDA) effectors in four pathways, three already implicated in follicle formation. They included Shh and its effectors, as well as antagonists for the Wnt (Dkk4) and BMP (Sostdc1) pathways. The fourth pathway was unexpected, a variant NF-kappa B-signaling cascade based on lymphotoxin-beta (LT beta)/ReIB. Previously known to participate only in lymphoid organogenesis, LT beta was enriched in developing hair follicles of WT but not in Ta mice. Furthermore, in mice lacking LT beta, all three types of mouse hair were still formed, but all were structurally abnormal. Guard hairs became wavy and irregular, zigzag/auchen hairs lost their kinks, and in a phenocopy of features of Ta animals, the awl hairs doubled in number and were characteristically distorted and pinched. LT beta-null mice that received WT bone marrow transplants maintained mutant hair phenotypes, consistent with autonomous LT beta action in skin independent of its expression in lymphoid cells. Thus, as an EDA target, LT beta regulates the form of hair in developing hair follicles; and when EDA is defective, failure of LT beta activation can account for part of the Ta phenotype.