Corneal morphogenesis during development and diseases.
OBJECTIVE
To review the use of genetically modified mouse lines for elucidating corneal morphogenesis during embryonic development and diseases.


METHODS
Transgenesis and gene-targeting techniques were used to create doxycycline-inducible mouse models (tet-On) to express transgenes or ablation of LoxP-modified genes or both in corneal cells, e.g., epithelial cells, and keratocytes and periocular mesenchymal cells of neural crest origin.


RESULTS
Two driver mouse lines, i.e., Krt12-rtTA and Kera-rtTA, were created, which express reverse tetracycline transcription activator (rtTA) in corneal epithelial cells and keratocytes, respectively. Bitransgenic (Krt12-rtTA/tet-o-FGF7) and triple transgenic mice (Krt12rtTA/tet-o-Cre/Ctnnb1 and Kera-rtTA/tet-o-Cre/Ctnnb1) were obtained through cross-breeding tet-o-FGF7, tet-o-Cre, and Ctnnb1 mice. On doxycycline induction, overexpression of FGF7 by corneal epithelial cells of bitransgenic Krt12-rtTA/tet-o-FGF7 mice caused nuclear translocation of beta-catenin and epithelium hyperplasia resembling human ocular surface squamous neoplasia; in triple transgenic mice (Krt12rtTA/tet-o-Cre/Ctnnb1), constitutive nuclear translocation of mutant beta-catenin (loss of exon 3) leads to hyper proliferation of corneal epithelial cells; in comparison of expression of beta-catenin mutant protein by migrating, periocular mesenchymal cells of Kera-rtTA/tet-o-Cre/Ctnnb1 caused eyelid malformation.


CONCLUSIONS
Use of genetically modified mice is of great value to study the pathophysiology of ocular surface defects resulting from genetic mutations.
Kao
Winston W-Y
WW
Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267-0838, USA. winston.kao@uc.edu
D000818:Animals; D003315:Cornea / Q000196:embryology* / Q000378:metabolism / Q000502:physiology; D003316:Corneal Diseases / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D019573:Epithelium, Corneal / Q000473:pathology; D006706:Homeostasis; D006965:Hyperplasia; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice / Q000196:embryology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009024:Morphogenesis; D009154:Mutation; D014178:Translocation, Genetic; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D036341:Intercellular Signaling Peptides and Proteins; D051176:beta Catenin