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V. Govindarajan, P.A. Overbeek; Inhibition of Protein Synthesis in the Lens in Transgenic Mice Leads to Loss of Corneal Endothelial Cells . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1239.
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Purpose: Experiments performed in chick embryos have led to the proposal that the lens makes an inducing signal that influences the development of surrounding ocular tissues. The purpose of this study was to genetically disrupt protein synthesis in the lens in mice and assess the developmental consequences. Methods: We have attempted to inhibit translation initiation in the lens by expression of an attenuated version of diptheria toxin (Tox176) in transgenic mice using a hybrid promoter (DREAM) that is active both in the undifferentiated epithelial and differentiated fiber cells. This promoter contains the regulatory elements of the chicken delta crystallin regulatory enhancer placed upstream from the mouse αA crystallin promoter followed by a noncoding minx intron (from adenovirus) and the polyA region from the αB crystallin at the 3’ end. Ocular development of wild type and transgenic mice was analyzed by standard histological techniques. Results: Two transgenic families (OVE1757 and 1758) that express the DREAMTox176 transgene have been generated. Adult transgenic mice in family OVE1757 are microphthalmic and mice in family OVE1758 form lens cataracts. In family OVE1757, necrotic lens fiber cells were seen by E15. These mice show multiple defects in the development of their anterior segments. There is a complete absence of the corneal endothelial layer along with disorganization and thickening of the corneal stroma. At birth, a disorganized group of cells was seen between the cornea and the lens. A rudimentary ciliary epithelium was noticed but iris formation was affected. No dramatic changes in retinal development were seen in either transgenic family. Conclusions: Expression of an attenuated version of diphtheria toxin in the lens leads to a gradual degeneration of the lens epithelial and fiber cells. This alters the differentiation program of the cornea and results in the loss of the corneal endothelium. These results confirm the prediction that a signal made by the lens in the murine eye is essential for the proper differentiation of the corneal endothelial cells.
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