Overexpression of zinc finger homeodomain 1 (Zeb1) triggers epithelial-mesenchymal transition (EMT) by repressing key epithelial specialization genes, including E-cadherin. By contrast, mutation of Zeb1 leads to mesenchymal-epithelial transition with ectopic expression of epithelial genes. Mutation of Zeb1 in patients is linked to epithelization of corneal endothelium and posterior polymorphous corneal dystrophy (PPCD). Mice null for Zeb1 exhibit PPCD characteristics late in embryogenesis, whereas such pathologic changes are delayed until adulthood in heterozygous mice. Overexpression of Zeb1 occurs in dedifferentiation of retinal pigment epithelial (RPE) cells, an EMT characterized by ectopic proliferation, loss of pigment and transition to fibroblastic morphology. Such RPE dedifferentiation contributes to proliferative vitreoretinopathy, the major complication in retinal detachment. Heterozygous mutation of Zeb1 prevents RPE dedifferentiation. We propose a series of experiments to begin examining the molecular basis for Zeb1 function in regulating epithelial-mesenchymal balance in eye cells.

Public Health Relevance

Epithelial vs. mesenchymal balance is crucial for normal tissue formation in development, and this balance is disrupted in eye diseases such as posterior corneal dystrophies and proliferative vitreoretinopathy. We provide evidence that the zinc finger E-box binding homeodomain1 (Zeb1) is important in regulating epithelial-mesenchymal balance in corneal endothelium and retinal pigmented epithelium.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EY019113-02
Application #
7663058
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mariani, Andrew P
Project Start
2008-08-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2011-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$222,000
Indirect Cost
Name
University of Louisville
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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