Role Of Ectodysplasin-a In Skin Appendage Formation

X连锁无汗性外胚层发育不良（EDA）是最常见的影响一个或多个皮肤附件的超过175外胚层发育不良。突变导致这种疾病的基因编码一种蛋白质，我们将其命名为外胚层发育不良-A，它具有一个单一的跨膜区，在一个长的细胞外羧基末端尾中具有胶原和TNF-配体片段。由于患有EDA的个体头发稀疏，牙齿发育不全，汗腺很少，因此该基因可能在发育的早期就参与其中。 我们证明，虎斑小鼠，它有许多在人类EDA中观察到的功能，是在相应的小鼠基因特异性突变。我们发现，在胚胎小鼠中提供编码外胚层发育不良的变异体的DNA可以恢复毛囊和汗腺。我们还表征了虎斑小鼠的眼睛表型，包括失明和炎症易感性，并且它们也通过补充相同的同种型而逆转。 在其他研究中，我们正在研究毛囊发育的最后阶段，我们正在研究小鼠模型中的人类疾病Carpellous Hair Hypoplasia。这些研究应该有助于维持或改革毛囊的尝试。 在机制研究中，我们已经表明EDA通过强大的NF-κ B信号通路激活四个主要的靶向通路，包括意料之外的参与，这是一种以前只知道有助于形成免疫系统器官的分子。 EDA和所有下游途径都需要继续已经启动的皮肤附件的发展。目前正在继续在小鼠模型中详细分析这一过程及其调节。这些模型包括对携带皮肤特异性转基因的小鼠的研究，这些转基因编码Dkk 4，Dkk 4似乎调节EdA的表达; Shh，这是EDA的主要靶点; Nemo，NF-kB通路的桥梁;和Troy，EDA作用的可能受体。

X-linked anhidrotic ectodermal dysplasia (EDA) is the most frequently occurring of more than 175 ectodermal dysplasias affecting one or more skin appendages. The gene that is mutated to cause this disorder encodes a protein, which we have named ectodysplasin-A, has a single transmembrane region with collagenous and TNF-ligand segments in a long extracelliular carboxyterminal tail. Because individuals with EDA have sparse hair, rudimentary teeth, and few sweat glands, the gene is likely involved at an early point in development. We demonstrated that the Tabby mouse, which has many of the features observed in human EDA, is specifically mutated in the corresponding mouse gene. We found that provision of DNA encoding a variant of ectodysplasin in embryonic mice rstores hair follicles and sweat glands. We also have characterized eye phenotypes of Tabby mice including blindness and inflammation susceptibility, and they are also reversed by supplementation with the same isoform. In additional studies to look at the final phases of hair follicle development, we are studying the human disease Cartilage Hair Hypoplasia in a mouse model. These studies should facilitate attempts to maintain or reform hair follicles. In mechanistic studies, we have shown that EDA acts through the powerful NF-kB signaling pathway to activate four major target pathways, including the unanticipated involvement of lymphotoxin-beta, a molecule previously only known to help form immune system organs. EDA and all of the downstream pathways are required to continue the development of already initiated skin appendages. Work is continuing to analyze the process and its regulation in detail in mouse models. The models include the study of mice bearing skin-specific transgenes encoding Dkk4, which appears to regulate EdA expression; Shh, which is a major target of EDA; Nemo, a bridge to the NF-kB pathway; and Troy, a possible receptor for EDA action.