Cui Chang-Yi, Hashimoto Tsuyoshi, Grivennikov Sergei I, Piao Yulan, Nedospasov Sergei A, Schlessinger David
Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9142-7. doi: 10.1073/pnas.0509678103. Epub 2006 May 31.
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-kappaB-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-kappaB-signaling cascade based on lymphotoxin-beta (LTbeta)/RelB. Previously known to participate only in lymphoid organogenesis, LTbeta was enriched in developing hair follicles of WT but not in Ta mice. Furthermore, in mice lacking LTbeta, 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. LTbeta-null mice that received WT bone marrow transplants maintained mutant hair phenotypes, consistent with autonomous LTbeta action in skin independent of its expression in lymphoid cells. Thus, as an EDA target, LTbeta regulates the form of hair in developing hair follicles; and when EDA is defective, failure of LTbeta activation can account for part of the Ta phenotype.
EDA基因突变会导致无汗/少汗型外胚层发育不良，这是一种在人类和小鼠模型“虎斑”（Ta）中表现为毛发、汗腺和牙齿形成缺陷的疾病。该基因编码外胚层发育不良蛋白，它是一种肿瘤坏死因子配体家族成员，可激活核因子κB信号通路，但对其下游靶点及皮肤附属器形成机制仅进行了部分分析。对野生型和Ta小鼠毛囊发育过程中的胚胎皮肤进行比较转录谱分析，确定了四条信号通路中的关键无汗/少汗型外胚层发育不良（EDA）效应因子，其中三条已被证实与毛囊形成有关。它们包括音猬因子（Shh）及其效应因子，以及Wnt信号通路（Dkk4）和骨形态发生蛋白信号通路（Sostdc1）的拮抗剂。第四条信号通路出人意料，是基于淋巴毒素β（LTβ）/RelB的一种变异核因子κB信号级联。此前已知LTβ仅参与淋巴器官的形成，它在野生型小鼠发育中的毛囊中富集，但在Ta小鼠中未富集。此外，在缺乏LTβ的小鼠中，三种类型的小鼠毛发仍能形成，但结构均异常。针毛变得波浪状且不规则，之字形/刚毛失去了弯曲，并且在Ta动物特征的拟表型中，锥形毛数量翻倍，且特征性地扭曲和变细。接受野生型骨髓移植的LTβ基因敲除小鼠维持了突变毛发表型，这与LTβ在皮肤中的自主作用一致，而与其在淋巴细胞中的表达无关。因此，作为EDA的靶点，LTβ在发育中的毛囊中调节毛发形态；当EDA有缺陷时，LTβ激活失败可部分解释Ta小鼠的表型。
