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X. Peng; Mutation of the Epithelial-Mesenchymal Transition Transcription Factor, Zeb1, Provides a Mouse Model of Posterior Cornea Dystrophy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1018.
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The zinc finger transcription factor, Zeb1, binds to E-box like sequences and is important for maintaining repression of epithelial specification genes in vivo. Overexpression of Zeb1 in cancer triggers epithelial-mesenchymal transition, which facilitates metastasis. Mutation of ZEB1 in humans is linked to posterior polymorphous corneal dystrophy (PPCD), where an epithelial transition of the corneal endothelium is associated with abnormal endothelial proliferation. The purpose of this study is to determine whether Zeb1 null or heterozygous mice may provide an animal model for PPCD.
Corneal morphology, protein and mRNA expression and cell proliferation were compared in wild-type and Zeb1 gene knockout mice by immunostaining, real time PCR and BrdU incorporation. mRNA expression in isolated embryo fibroblasts derived from wild-type, Zeb1 heterozygous and null mice was analyzed by real time PCR
Zeb1 null mice late in gestation show ectopic expression of epithelial genes in the corneal endothelium and keratocytes, including the basement membrane component, COL4A3, which is ectopically expressed by the corneal endothelium in PPCD. These embryos also show abnormal corneal endothelial and keratocyte proliferation, corneal thickening, and corneolenticular and iridocorneal adhesions. Adult Zeb1 heterozygous mice exhibit these same corneal defects. The ectopic expression of epithelial genes extended to embryonic fibroblasts derived from Zeb1 heterozygous and null mice, suggesting that Zeb1 may have a more general role in suppression of an epithelial phenotype.
We conclude that Zeb1 heterozygous and null mice show features of PPCD, and thus should provide an animal model for genetic dissection of pathways contributing to the disease.
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