title: Zeb1 mutant mice as a model of posterior corneal dystrophy.
abstract: OBJECTIVE
  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. The mutation of ZEB1 in humans is linked to posterior polymorphous corneal dystrophy (PPCD), in which 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.
  
  
  METHODS
  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 RESULTS: 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 the suppression of an epithelial phenotype.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, 301 E. Muhammad Ali Boulevard, Louisville, KY 40202, USA.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Peng
authors.forename: Jinlian
authors.initials: J
authors.lastname: Tan
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Darling
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Kaplan
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Dean
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D003317:Corneal Dystrophies, Hereditary / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D004728:Endothelium, Corneal / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D019573:Epithelium, Corneal / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D018628:Gene Dosage; D005838:Genotype; D018398:Homeodomain Proteins / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071799:Zinc Finger E-box-Binding Homeobox 1; D016335:Zinc Fingers / Q000502:physiology*
chemical_list: D001324:Autoantigens; D015820:Cadherins; D024141:Collagen Type IV; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; C057112:type IV collagen alpha3 chain; D001973:Bromodeoxyuridine