Ectodysplasin receptor-mediated signaling is essential for embryonic submandibular salivary gland development
Ectodysplasin receptor-mediated signaling is essential for embryonic submandibular salivary gland development
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DOI：
10.1002/ar.a.10045
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发表时间：
2003-04-01
期刊：
影响因子：
--
通讯作者：
Melnick, M
中科院分区：
文献类型：
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作者：
Jaskoll, T;Zhou, YM;Melnick, M
无汗性外胚层发育不良(HED)是150种类似外胚层发育不良中最常见的一种，是一种以毛发、牙齿、汗腺和唾液腺异常为特征的疾病。EDA基因突变和EDAR基因突变分别导致X连锁和常染色体HED。类似于Hed的异常表型在猫(edA(Ta))和Downless(Edar(Dl))突变小鼠中可见。虽然最近的研究主要集中在EDA/EDAR信号在毛发和牙齿发育中的作用，但对其在胚胎颌下腺(SMG)发育中的作用知之甚少。为此，我们分析了猫(Ta)和羽绒(Dl)突变小鼠的SMG表型，确定Ta SMGs发育不良，而dl SMGs发育严重异常。Dl SMGs中缺少SMG导管和腺泡，提示EDA/EDAR信号通路对管腔的形成和腺体的组织分化是必不可少的。我们对Eda和Edar蛋白在腔和腺泡形成部位的定位支持这一结论。此外，在Ta和dl突变小鼠中都存在SMGs，以及在初芽和假腺体早期SMGs中没有免疫检测到的EDA和Edar蛋白，这表明EDA/Edar介导的信号对分支形态发生和组织分化很重要，但对初级腺形成不重要。为了初步阐明EDA/EDAR介导的信号在胚胎SMG发育中的形态调节作用，我们培养了第14天的胚胎SMG，增强或取消了EDA/EDAR信号。补充EDA后，SMG分枝明显增加，并增强了NF-kappaB的活性。在胚胎SMGs中加入EDAR的可溶性形式来结合内源配体来取消EDA/EDAR信号转导，导致明显的剂量依赖性的分枝形态发生减少。综上所述，我们的结果提示EDA/Edar/NF-kappaB通路在SMG上皮细胞的增殖、管腔形成和组织分化中发挥作用。(C)2003年Wiley-Liss，Inc.
Hypohidrotic (anhidrotic) ectodermal dysplasia (HED), the most common of the similar to150 described ectodermal dysplasias, is a disorder characterized by abnormal hair, teeth, sweat glands, and salivary glands. Mutations in the EDA (ectodysplasin-A) and EDAR (ectodysplasin-A receptor) genes are responsible for X-linked and autosomal HED, respectively. Abnormal phenotypes similar to HED are seen in Tabby (Eda(Ta)) and downless (Edar(dl)) mutant mice. Although recent studies have focused on the role of Eda/Edar signaling during hair and tooth development, very little is known about its role during embryonic submandibular salivary gland (SMG) development. To this end, we analyzed the SMG phenotypes in Tabby (Ta) and downless (dl) mutant mice and determined that Ta SMGs are hypoplastic, whereas dl SMGs are severely dysplastic. The absence of SMG ducts and acini in dl SMGs suggests that Eda/Edar signaling is essential for lumina formation and glandular histodifferentiation. Our localization of Eda and Edar proteins at sites of lumen and acini formation supports this conclusion. Moreover, the presence of SMGs in both Ta and dl mutant mice, as well as the absence of immunodetectable Eda and Edar protein in Initial Bud and Early Pseudoglandular stage SMGs, indicate that Eda/Edar-mediated signaling is important for branching morphogenesis and histodifferentiation, but not for initial gland formation. To initially delineate the morphoregulatory role of Eda/Edar-mediated signaling during embryonic SMG development, we cultured embryonic day 14 SMGs with enhanced or abrogated Eda/Edar signaling. Eda supplementation induced a significant increase in SMG branching, and enhanced activation of NF-kappaB. Abrogating Eda/Edar signaling by adding the soluble form of Edar to bind endogenous ligand in embryonic SMGs results in a significant dose-dependent decrease in branching morphogenesis. Taken together, our results suggest that the Eda/Edar/NF-kappaB pathway exerts its effect on SMG epithelial cell proliferation, lumina formation, and histodifferentiation. (C) 2003 Wiley-Liss, Inc.