Ectoderm-targeted overexpression of the glucocorticoid receptor induces hypohidrotic ectodermal dysplasia
Ectoderm-targeted overexpression of the glucocorticoid receptor induces hypohidrotic ectodermal dysplasia
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DOI：
10.1210/en.2004-1246
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发表时间：
2005-06-01
期刊：
影响因子：
4.8
通讯作者：
Pérez, P
中科院分区：
文献类型：
--
作者：
Cascallana, JL;Bravo, A;Pérez, P
少汗性外胚层发育不良是一种人类综合征，定义为一个或多个外胚层衍生组织发育不良，包括表皮和皮肤附件、牙齿和外分泌腺。这种病理学的分子基础集中于 B 细胞中 kappa 增强子的转录因子核因子 (NF-kappa B) 的功能障碍，这对于上皮稳态和发育至关重要。据报道，许多 NF-κ B 信号传导中断的小鼠模型都表现出外胚层衍生物的缺陷。在过度表达糖皮质激素受体（GR）的外胚层靶向转基因小鼠[角蛋白5（K5）-GR小鼠]中，由于GR和NF-κB之间的功能拮抗作用，NF-κB活性大大降低。在此，我们报告K5-GR小鼠在毛囊、牙齿和腭发育中表现出多种上皮缺陷。此外，这些小鼠缺乏睑板腺，并且汗腺和包皮腺发育不全。这些表型特征似乎是由配体激活的 GR 特异性介导的，因为合成类似物地塞米松在野生型小鼠中诱导了上皮形态发生（包括牙发育）的类似缺陷。我们重点关注 K5-GR 小鼠的牙齿发育，发现类固醇合成抑制剂部分逆转了异常表型。免疫染色显示 K5-GR 胚牙中 kappa B 激酶亚基抑制剂 IKK α 和 IKK γ 的表达降低，p65 蛋白水平降低，导致 kappa B 结合活性显着降低。值得注意的是，GR 过表达引起的 NF-kappa B 活性改变与牙齿上皮细胞中 Delta Np63 蛋白水平的急剧下降相关，而不影响 Akt、BMP4 或 Foxo3a。鉴于 170 种临床上不同的外胚层发育不良综合征中的许多仍然没有同源基因，破译这种具有上皮 NF-κB 和 p63 功能障碍的小鼠模型的分子机制可能为了解其他外胚层发育不良综合征的基础提供重要线索。
Hypohidrotic ectodermal dysplasia is a human syndrome defined by maldevelopment of one or more ectodermal-derived tissues, including the epidermis and cutaneous appendices, teeth, and exocrine glands. The molecular bases of this pathology converge in a dysfunction of the transcription factor nuclear factor of the kappa-enhancer in B cells (NF-kappa B), which is essential to epithelial homeostasis and development. A number of mouse models bearing disruptions in NF-kappa B signaling have been reported to manifest defects in ectodermal derivatives. In ectoderm-targeted transgenic mice overexpressing the glucocorticoid receptor (GR) [ keratin 5 (K5)-GR mice], the NF-kappa B activity is greatly decreased due to functional antagonism between GR and NF-kappa B. Here, we report that K5-GR mice exhibit multiple epithelial defects in hair follicle, tooth, and palate development. Additionally, these mice lack Meibomian glands and display underdeveloped sweat and pre-putial glands. These phenotypic features appear to be mediated specifically by ligand-activated GR because the synthetic analog dexamethasone induced similar defects in epithelial morphogenesis, including odontogenesis, in wild-type mice. We have focused on tooth development in K5-GR mice and found that an inhibitor of steroid synthesis partially reversed the abnormal phenotype. Immunostaining revealed reduced expression of the inhibitor of kappa B kinase subunits, IKK alpha and IKK gamma, and diminished p65 protein levels in K5-GR embryonic tooth, resulting in a significantly reduced kappa B-binding activity. Remarkably, altered NF-kappa B activity elicited by GR overexpression correlated with a dramatic decrease in the protein levels of Delta Np63 in tooth epithelia without affecting Akt, BMP4, or Foxo3a. Given that many of the 170 clinically distinct ectodermal dysplasia syndromes still remain without cognate genes, deciphering the molecular mechanisms of this mouse model with epithelial NF-kappa B and p63 dysfunction may provide important clues to understanding the basis of other ectodermal dysplasia syndromes.