No abstract

This review gives a brief account of the main processes of lens development, including induction, morphogenesis, differentiation and growth. It describes what is known about the molecules and mechanisms that control and regulate these processes. Some of the recent progress made in understanding the molecular basis of lens development is highlighted along with some of the challenging areas for future research.

Spindle-shaped myofibroblast-like cells, which contain alpha-smooth muscle actin, have been described in anterior subcapsular cataract and after-cataract. In a previous study in this laboratory, it was shown that transforming growth factor-beta (TGF beta) induces the formation of spindle-shaped cells in lens epithelial explants. The aim of this investigation was to determine whether these TGF beta-induced spindle-shaped cells contain alpha-smooth muscle actin. Lens epithelial explants were prepared from 21-day-old rats and cultured with either TGF beta 1 or basic FGF alone, a combination of both growth factors, or without added growth factors. After three days, cellular changes were monitored by phase contrast microscopy, localisation of filamentous actin with rhodamine-phalloidin, and immunolocalisation and immunoblotting of alpha-smooth muscle actin. TGF beta induced rapid cell elongation and formation of characteristic spindle-shaped cells in lens epithelial explants in the presence or absence of FGF. These cells contained alpha-smooth muscle actin, a marker for myofibroblastic cells and a protein not normally found in the lens. The present study thus provides molecular evidence that TGF beta induces cataractous changes in lens epithelial cells. As TGF beta is potentially available to lens cells in situ throughout life, these findings are consistent with a key role for TGF beta in the aetiology of major forms of subcapsular cataract.

Explants of epithelial cells from newborn rat lenses undergo changes characteristic of fibre differentiation when cultured with neural retina or retina-conditioned medium. Here we show that similar changes occur when acidic and basic fibroblast growth factor (FGF) are used instead of retina-conditioned medium. When cultured without FGF, epithelial explants contained negligible amounts of beta-crystallin, a lens protein found only in fibre cells. However, at saturating concentrations of FGF, about 20 micrograms beta-crystallin was produced per explant in 5 days. The response was dose-dependent, half maximal response requiring 55 and 290 ng/ml of basic and acidic FGF, respectively. FGF also stimulated cell proliferation and cell migration. All three responses to basic FGF were blocked by an antibody specific for basic FGF. The concentration of FGF required to produce a maximal response was lower for cell proliferation and migration than for beta-crystallin accumulation. The results suggest a possible role for FGF in the control of events in lens development.

Cataract, already a major cause of visual impairment and blindness, is likely to become an increasing problem as the world population ages. In a previous study, we showed that transforming growth factor-β (TGFβ) induces rat lenses in culture to develop opacities and other changes that have many features of human subcapsular cataracts. Here we show that estrogen protects against cataract. Lenses from female rats are more resistant to TGFβ-induced cataract than those from males. Furthermore, lenses from ovariectomized females show increased sensitivity to the damaging effects of TGFβ and estrogen replacement in vivo, or exposure to estrogen in vitro, restores resistance. Sex-dependent and estrogen-related differences in susceptibility to cataract formation, consistent with a protective role for estrogen, have been noted in some epidemiological studies. The present study in the rat indicates that estrogen provides protection against cataract by countering the damaging effects of TGFβ. It also adds to an increasing body of evidence that hormone replacement therapy protects postmenopausal women against various diseases.