Requirement for TGF beta receptor signaling during terminal lens fiber differentiation

Several families of growth factors have been identified as regulators of ce ll fate in the developing lens. Members of the fibroblast growth factor fam ily are potent inducers of lens fiber differentiation. Members of the trans forming growth factor beta (TGF beta) family, particularly bone morphogenet ic 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, TGF beta family members have been sho wn to induce pathological changes in lens epithelial cells similar to those seen in forms of human subcapsular cataract. Previous studies have shown t hat type I and type H TGF beta receptors, in addition to being expressed in the epithelium, are also expressed in patterns consistent with a role in l ens fiber differentiation. In this study we have investigated the consequen ces of disrupting TGF beta signaling during lens fiber differentiation by u sing the mouse alphaA-crystallin promoter to overexpress mutant (kinase def icient), dominant-negative forms of either type I or type II TGF beta recep tors in the lens fibers of transgenic mice. Mice expressing these transgene s had pronounced bilateral nuclear cataracts. The phenotype was characteriz ed by attenuated lens fiber elongation in the cortex and disruption of fibe r differentiation, culminating in fiber cell apoptosis and degeneration in the lens nucleus. Inhibition of TGF beta signaling resulted in altered expr ession patterns of the fiber-specific proteins, alpha -crystallin, filensin , phakinin and MIR In addition, in an in vitro assay of cell migration, exp lanted 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 TGF beta signaling is a key event during fiber differentiation and is required for completion of terminal differenti ation.