Corneal Morphogenesis During Development and Diseases

Abstract

To review the use of genetically modified mouse lines for elucidating corneal morphogenesis during embryonic development and diseases. 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. 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. Use of genetically modified mice is of great value to study the pathophysiology of ocular surface defects resulting from genetic mutations.