Molecular Regulation of Epithelial-Mesenchymal Transitions

人类ZFHX1A锌指同源结构域转录抑制因子杂合突变导致后部多形性角膜营养不良，这是一种角膜内皮的病理性上皮化。在突变小鼠中，角膜内皮也存在上皮样向间充质样过渡性缺陷，E钙粘附素表达增强，波形蛋白表达缺失。在胚胎视网膜、视神经、软骨间充质和脑室下区，这种上皮/外胚层与间充质的过渡缺陷也很明显。这些缺陷的特征还包括上皮标志物E-钙粘素的扩张和血管内皮细胞的收缩 间充质/外胚层标记物Vimentin和GFAP。在这些受影响的部位，也有细胞增殖抑制基因的诱导，因此在注射BrdU的小鼠的突变胚胎组织中，这些部位的增殖受到抑制。从突变胚胎培养的细胞中可以重现类似的上皮和间质转化缺陷，并且增殖性缺陷也是明显的，从而为研究ZFHX1A的作用提供了一个培养模型。我们提出了一系列实验来评估ZFHX1a转录调控的机制，从而在体内和培养细胞中确定上皮和间充质表型之间的平衡以及控制细胞增殖的分子作用。

Heterozygous mutations in the ZFHX1A zinc finger homeodomain transcriptional repressor in humans cause posterior polymorphous corneal dystrophy, a pathologic epithelization of the corneal endothelium. In mutant mice there are also epithelial vs. mesenchymal-like transition defects in the corneal endothelium, with acquisition of E cadherin expression and loss of vimentin expression. Such epithelial/ectodermal vs. mesenchymal transition defects are also evident in the embryonic retina, optic nerve, cartilage mesenchyme and subventricular zones of the brain. These defects are also characterized by expansion of the epithelial marker E-cadherin and contraction of the mescenchymal/ectodermal markers vimentin and GFAP. At these affected sites, there is also induction of cell proliferation inhibitor genes, and accordingly diminished proliferation is seen at these sites in mutant embryonic tissues in mice injected with BrdU. Similar epithelial vs. mesenchymal transition defects are recapitulated in cells cultured from mutant embryos, and the proliferative defects are also evident, thereby providing a culture model to study the biochemistry of ZFHX1A action. We propose a series of experiments to assess the mechanism of transcriptional control by ZFHX1a and thus its molecular role in defining a balance between epithelia vs. mesenchymal phenotype and control of cell proliferation in vivo and in cultured cells.