Zeb1 and epithelial-mesenchymal balance in the eye

描述(申请人提供)：过表达锌指同源域1(ZEB1)通过抑制关键的上皮特化基因，包括E-钙粘素，触发上皮-间充质转化(EMT)。相反，ZEB1基因突变导致间充质-上皮细胞转化，并导致上皮基因的异位表达。患者ZEB1基因突变与角膜内皮上皮化和后部多形性角膜营养不良(PPCD)有关。ZEB1基因缺失的小鼠在胚胎发育后期表现出PPCD特征，而杂合子小鼠的这种病理变化会推迟到成年。ZEB1的过度表达发生在视网膜色素上皮(RPE)细胞的去分化过程中，RPE是一种以异位增殖、色素丢失和向成纤维细胞形态转变为特征的EMT。这种RPE去分化导致增殖性玻璃体视网膜病变，这是视网膜脱离的主要并发症。ZEB1杂合突变可阻止RPE去分化。我们提出了一系列实验，以开始研究ZEB1在调节眼细胞上皮-间充质平衡中功能的分子基础。公共卫生相关性：上皮和间质的平衡对于发育过程中正常的组织形成至关重要，这种平衡在眼科疾病中被破坏，如角膜后营养不良和增殖性玻璃体视网膜病变。我们提供的证据表明，锌指E盒结合同源结构域1(ZEB1)在调节角膜内皮和视网膜色素上皮的上皮-间充质平衡中起重要作用。

DESCRIPTION (provided by applicant): Overexpression of zinc finger homeodomain 1 (Zeb1) triggers epithelial-mesenchymal transition (EMT) by repressing key epithelial specialization genes, including E-cadherin. By contrast, mutation of Zeb1 leads to mesenchymal-epithelial transition with ectopic expression of epithelial genes. Mutation of Zeb1 in patients is linked to epithelization of corneal endothelium and posterior polymorphous corneal dystrophy (PPCD). Mice null for Zeb1 exhibit PPCD characteristics late in embryogenesis, whereas such pathologic changes are delayed until adulthood in heterozygous mice. Overexpression of Zeb1 occurs in dedifferentiation of retinal pigment epithelial (RPE) cells, an EMT characterized by ectopic proliferation, loss of pigment and transition to fibroblastic morphology. Such RPE dedifferentiation contributes to proliferative vitreoretinopathy, the major complication in retinal detachment. Heterozygous mutation of Zeb1 prevents RPE dedifferentiation. We propose a series of experiments to begin examining the molecular basis for Zeb1 function in regulating epithelial-mesenchymal balance in eye cells. PUBLIC HEALTH RELEVANCE: Epithelial vs. mesenchymal balance is crucial for normal tissue formation in development, and this balance is disrupted in eye diseases such as posterior corneal dystrophies and proliferative vitreoretinopathy. We provide evidence that the zinc finger E-box binding homeodomain1 (Zeb1) is important in regulating epithelial-mesenchymal balance in corneal endothelium and retinal pigmented epithelium.