CONTROL OF CORNEAL ENDOTHELIUM DEVELOPMENT IN THE MOUSE

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The goal of this study is to define the role of Mf1, a forehead/winged helix transcription factor, in the development of the cornea of the mammalian eye. We have previously shown that in mouse embryos lacking a functional Mf1 gene (generated either by homologous recombination-Mf1/lacZ-or as a result of spontaneous mutation-Mf1/Ch) the corneal endothelium fails to differentiate from the embryonic corneal mesenchyme. This is accompanied by a number of other eve developmental abnormalities, including failure of anterior chamber formation, iris dystrophy, and abnormalities of the trabecular meshwork (Kidson et al, 1999, Appendix). The failure to form a corneal endothelium in these mutants thus provides an ideal system for investigate the normal development of the corneal endothelium in vivo, about which little is known. The human homologue of the mouse Mf1 gene (known as FKHL/FREAC3) has recently been cloned by two groups. Dominant mutations in this gene have been shown to be associated with inherited anterior segment defects, including hypoplasia of the iris, dysgenesis of the anterior angle and trabecular meshwork, corneal opacity and increased risk of juvenile onset congenital glaucoma (Axenfeld-Rieger Anomaly, Mears et al, 1998: Nishimura et al, 1998). In addition, several inherited disorders of the cornea have been reported to humans. For example, congenital hereditary endothelial dystrophy, a condition that can be either autosomal dominant or recessive, is associated with absence of the endothelium, thickening of the stroma and corneal opacity (Mullany et al, 1995: Kirkness et al, 1987). Thus, the proposed studies will lead to a better understanding of human eye defects associated with corneal endothelium failure, including glaucoma and corneal endothelial dystrophy. The hypothesis will be tested that Mf1 functions in the corneal mesenchyme as part of the downstream signaling pathway from as yet unidentified factors secreted by the embryonic lens. The techniques to be used will include in vitro culture and differentiation of normal and mutant corneal mesenchyme, co-culture with embryonic lens, addition of growth factors, and screening for Mf1 regulated genes.