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Y Xia, L Zhang, Y Hayashi, CW C Kao, C-Y Liu, D Birk, JV Jester, WW Y Kao; Role of MEKK1 in Mouse Ocular Surface Morphogenesis . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2000.
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Purpose: Ablation of MEK kinase 1 (MEKK1) in mice results in eye-open at birth (EOB), due to impaired embryonic eyelid closure. Mekk1-mutant mice exhibit severe eye pathologies that affect cornea, conjunctiva, lens and retina. This study is aimed at identifying the cellular and molecular changes regulated by MEKK1 that are essential for eyelid morphogenesis. Methods: Eyes of wild type and Mekk1-mutant embryos were subjected to scanning electron microscopy (EM) and transmission EM analyses. Whole mount FITC Phalloidin labeling was performed on wild type, Mekk1(+/-) and Mekk1(-/-) embryonic eyes and observed by confocal microscopy. The expression of ZO-1 was examined by immunohistochemistry. cDNA microarray analysis was carried out using RNA isolated from eyelids of Mekk1(+/-) versus Mekk1(-/-) embryos. Results: Scanning EM show, in the wild type and Mekk1(+/-) embryos of gestation days 14 to 15.5, the appearance of epithelial cell bleb at the leading edge of growing eyelid, an indication of individual epithelial cell transformation and acquisition of motility. Such epithelial changes do not occur in Mekk1(-/-) eyelids. Fundamental differences between wild type and Mekk1(-/-) eyelid epithelium have also been demonstrated by transmission EM studies. During lid closure, the wild type exhibits loss and reduced epithelial cell-cell contact, in contrast to the high cell density and tight cell interactions found in Mekk1(-/-). Consistent with these observations, the eyelid of Mekk1(-/-) embryo lack a well developed actin filament network and absent in ZO-1 expression in migrating epithelial sheet, possible markers for transdifferentiation of epithelium to mesenchyme. In contrast, prominent circumferential actin filaments and ZO-1 in the developing eyelid are observed in wild type, and to a lesser extent in Mekk1(+/-) emrbyos during eyelid formation. cDNA microarray analysis has identified several potential target genes that may be connected to epithelial differentiation and epithelial-mesenchymal transition. Conclusion: Epithelial-to-mesenchymal transition (EMT) allows epithelial sheet migration in tissue morphogenesis during embryonic development, e.g., fusion of palate. Our data suggest that mouse embryonic eyelid closure requires EMT, which is likely to be regulated by MEKK1. The eyelid closure defect in Mekk1(-/-) may be caused by impaired EMT during eyelid development.
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