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.
Transition of cells from and epithelial to a mesenchymal phenotype is a key initiator in all fibrotic diseases. And, it also initiates a metastatic phenotype in late stage cancers. A set of transcription factors including ZFHX1a regulate epithelial and mesenchymal genes to control normal epithelial vs. mesenchymal balance in vivo, and deregulation of these factors is important for initiation of fibrotic disease and cancer metastasis. Studies proposed here are directed at the molecular mechanism of how ZFHX1a regulates transcription. Such fundamental knowledge should provide a foundation for developing therapeutic approaches aimed at controlling fibrotic disease and cancer metastasis.
