Conservation of fibroblast growth factor function in lens regeneration

Abstract

In urodele amphibians, lens induction during development and regeneration occurs through different pathways. During development, the lens is induced from the mutual interaction of the ectoderm and the optic vesicle, whereas after lentectomy the lens is regenerated through the transdifferentiation of the iris-pigmented epithelial cells. Given the known role of fibroblast growth factors (FGFs) during lens development, we examined whether or not the expression and the effects of exogenous FGF during urodele lens regeneration were conserved. In this paper, we describe expression of FGF-1 and its receptors, FGFR-2 (KGFR and bek variants) and FGFR-3, in newts during lens regeneration. Expression of these genes was readily observed in the dedifferentiating pigmented epithelial cells, and the levels of expression were high in the lens epithelium and the differentiating fibers and lower in the retina. These patterns of expression implied involvement of FGFs in lens regeneration. To further elucidate this function, we examined the effects of exogenous FGF-1 and FGF-4 during lens regeneration. FGF-1 or FGF-4 treatment in lentectomized eyes resulted in the induction of abnormalities reminiscent to the ones induced during lens development in transgenic mice. Effects included transformation of epithelial cells to fiber cells, double lens regeneration, and lenses with abnormal polarity. These results establish that FGF molecules are key factors in fiber differentiation, polarity, and morphogenesis of the lens during regeneration even though the regenerating lens is induced by a different mechanism than in lens development. In this sense, FGF function in lens regeneration and development should be regarded as conserved. Such conservation should help elucidate the mechanisms of lens regeneration in urodeles and its absence in higher vertebrates.

Beyond early development: Xenopus as an emerging model for the study of regenerative mechanisms

“…Fgf-2 (basic Fgf) has been shown to induce chick pigmented epithelial cells to transdifferentiate into lens fibers, suggesting a conserved mechanism (Hyuga et al, 1993). There are also studies demonstrating up-regulation of Fgf receptors in lens regeneration (Del Rio- Tsonis et al, 1997;McDevitt et al, 1997;Arresta et al, 2005). Fgf signaling is, therefore, a strong candidate for initiating transdifferentiation in competent tissues, but whether or not it is indispensible for the process has yet to be determined.…”

The role of Pax-6 in lens regeneration

“…However, the continued expression of genes involved in embryonic lens induction in the adult newt suggests that some genes may be involved in both processes. Indeed, lens differentiation-controlling genes such as FGFs, Pax-6, Sox-2, MafB, and Prox-1 have been found in both dorsal and ventral irises of intact as well as regenerating newt eyes (10)(11)(12)(13)(14). Even though it has been established that the Pax-6 gene is expressed during the process of lens regeneration, a direct association with events of regeneration has never been established (10,13,14).…”

Signaling during lens regeneration

“…Del RioTsonis and colleagues were the first to show the production of a second lens after FGF4 treatment in lentectomized eyes. Treatment of lentectomized newts with both FGF1 and FGF4 induced lenses with abnormal polarity due to differentiation of lens epithelial cells to lens fibers, and double lens formation from the dorsal iris [16]. These abnormalities in the regenerating lenses appeared to be similar to the lens polarity abnormalities induced during lens development in transgenic FGF mice [17].…”

“…Several FGF receptors are expressed including FGFR1, FGFR2, and FGFR3 [16,23,24]. Detailed examination of the receptors, showed that FGFR-1 is confined to the dedifferentiating dorsal iris and plays a role in regulating lens regeneration.…”