Molecular Regulation of Epithelial-Mesenchymal Transitions

人类ZFHX 1A锌指同源结构域转录抑制因子的杂合突变可导致后部多形角膜营养不良，这是一种角膜内皮的病理性上皮化。在突变小鼠中，角膜内皮中也存在上皮与间充质样转变缺陷，E钙粘蛋白表达获得和波形蛋白表达丧失。这种上皮/外胚层与间充质转化缺陷在胚胎视网膜、视神经、软骨间充质和脑的脑室下区中也是明显的。这些缺陷的特征还在于上皮标记物E-钙粘蛋白的扩张和上皮细胞的收缩。 间充质/外胚层标记物波形蛋白和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，在这些部位观察到增殖减少。类似的上皮与间充质转化缺陷在从突变胚胎培养的细胞中重现，并且增殖缺陷也是明显的，从而提供了研究ZFHX 1A作用的生物化学的培养模型。我们提出了一系列实验来评估ZFHX 1a的转录控制机制，从而评估其在定义上皮细胞与间充质细胞表型之间的平衡以及体内和培养细胞中细胞增殖控制方面的分子作用。

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.