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1 Department of Anatomy and Histology, The University of Sydney, NSW 2006, Australia
2 Save Sight Institute, The University of Sydney, NSW 2006, Australia
3 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
4 Department of Medicine, Baylor College of Medicine, Houston, TX, USA
5 Children’s Medical Research Institute, Westmead Hospital, Westmead NSW 2145, Australia
*Author for correspondence (e-mail: robbdei{at}anatomy.usyd.edu.au)
Accepted July 24, 2001
Several families of growth factors have been identified as regulators of cell fate in the developing lens. Members of the fibroblast growth factor family are potent inducers of lens fiber differentiation. Members of the transforming growth factor ß (TGFß) family, particularly bone morphogenetic proteins, have also been implicated in various stages of lens and ocular development, including lens induction and lens placode formation. However, at later stages of lens development, TGFß family members have been shown to induce pathological changes in lens epithelial cells similar to those seen in forms of human subcapsular cataract. Previous studies have shown that type I and type II TGFß receptors, in addition to being expressed in the epithelium, are also expressed in patterns consistent with a role in lens fiber differentiation. In this study we have investigated the consequences of disrupting TGFß signaling during lens fiber differentiation by using the mouse 
A-crystallin promoter to overexpress mutant (kinase deficient), dominant-negative forms of either type I or type II TGFß receptors in the lens fibers of transgenic mice. Mice expressing these transgenes had pronounced bilateral nuclear cataracts. The phenotype was characterized by attenuated lens fiber elongation in the cortex and disruption of fiber differentiation, culminating in fiber cell apoptosis and degeneration in the lens nucleus. Inhibition of TGFß signaling resulted in altered expression patterns of the fiber-specific proteins, -crystallin, filensin, phakinin and MIP. In addition, in an in vitro assay of cell migration, explanted lens cells from transgenic mice showed impaired migration on laminin and a lack of actin filament assembly, compared with cells from wild-type mice. These results indicate that TGFß signaling is a key event during fiber differentiation and is required for completion of terminal differentiation.
Key words: Lens, Differentiation, TGFß, TGFß receptors, Transgenesis, Mouse
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