Zeb1 Mutant Mice as a Model of Posterior Corneal Dystrophy

Abstract

The authors 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.

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

“…ZEB1( À / À ) mice are not viable, but ZEB1( þ / À ) mice, which express approximately half the level of ZEB1, are viable 10,15 . Heterozygous mutation of ZEB1 is responsible for corneal dystrophy in mice and humans, and patients with this mutation also show increased risk for hernia, hydrocele and aneurysm 16,17 . Thus, a partial decrease in ZEB1 resulting from mutation of one allele is biologically significant, implying a narrow threshold linking ZEB1 expression to at least some functions.…”

Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3

“…31 Conversely, enhanced expression of epithelial-specific genes in this pathway, including E-cadherin (CDH1) and COL4A3, has been demonstrated in embryonic null and adult haploinsufficient ZEB1 mice. 20,30 Importantly, the mice display abnormal corneal endothelial and keratocyte proliferation, as well as abnormal posterior corneal morphology, mimicking the PPCD3 phenotype. 30 Interestingly, the corneal endothelium from PPCD3 patients exhibits increased expression of markers for an epithelial cell phenotype, such as keratins 7 and 19.…”

“…20,30 Importantly, the mice display abnormal corneal endothelial and keratocyte proliferation, as well as abnormal posterior corneal morphology, mimicking the PPCD3 phenotype. 30 Interestingly, the corneal endothelium from PPCD3 patients exhibits increased expression of markers for an epithelial cell phenotype, such as keratins 7 and 19. 2,3 Patients with PPCD also have multilayering of the corneal endothelium that is probably due to uncontrolled growth of a dividing endothelium.…”

“…30 Interestingly, overexpression of ZEB1 in cancers has been shown to trigger EMT by ZEB1-mediated repression of epithelial-specific genes. 31 Conversely, enhanced expression of epithelial-specific genes in this pathway, including E-cadherin (CDH1) and COL4A3, has been demonstrated in embryonic null and adult haploinsufficient ZEB1 mice.…”

Expression of ZEB factors in oral squamous cell carcinoma.

“…The ZEB1 null mutant mice survive through embryonic development, but apparently die immediately after birth suggesting a defect in the ability to breathe (Takagi, Moribe et al 1998). ZEB1 knockout mice have also demonstrated abnormal corneal epithelium due to the suppression of the epithelial phenotype (Liu, Peng et al 2008). In humans, a ZEB1 mutation can cause posterior polymorphous corneal dystrophy because of aberrant corneal endothelium; this mutation is relatively rare and is dominant (Lechner, Dash et al 2013).…”