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.
