FGF2 triggers iris-derived lens regeneration in newt eye

Abstract

Lens regeneration in newts occurs exclusively from the dorsal aspect of the iris pigment epithelium. Although the phenomenon has been a paradigm of experimental tissue regeneration, little is understood about how it is initiated and restricted to the dorsal iris. Here we show among various growth factors injected in an intact eye, a single injection of FGF2 specifically caused morphological changes of the iris characteristic of lens regeneration, induced expression of transcription factor genes Pax6, Sox2 and MafB, as well as endogenous Fgf2 in both dorsal and ventral halves, and provoked second lens development only from the dorsal iris. FGF2 protein accumulated in the iris tissue after the lens was removed, and injection of a soluble form of FGF receptor titrating FGF2 inhibited all reactions observed after the lens removal or after administration of FGF2. These results indicate that FGF2 and/or related molecules trigger lens regeneration from the dorsal iris in the newt. The observations also indicate that the absence of lens regeneration from the ventral iris is due to a block in a later phase of lens developmental pathway.

Foxe view of lens development and disease

“…While this possibility is under investigation, it has already been demonstrated that primate ES cells can be directed to form Pax6-and ␣A-crystallin-expressing lentoid bodies after treatment with FGF2 (Ooto et al, 2003). FGF2 triggers lens regeneration in newt (Hayashi et al, 2004), and FGF molecules and their receptors are known to play a role in different aspects of lens formation (for…”

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

“…Hayashi and colleagues have shown that intraocular injection of recombinant FGF2 can trigger lens regeneration from the dorsal iris without previously removing the host lens. Injection of FGF2 also induced expression of several transcription factors such as Pax6, Sox2, and MafB [19]. Intraocular injections of recombinant newt FGF1 also had effects on newt lens regeneration [20].…”

“…However, transfection of FGFR-1 into cultured newt iris PECs (dorsal and ventral) with subsequent re-implantation into host newts did not induce lens regeneration from the ventral iris (0/11 -0%) and had no observable effect on lens regeneration from the dorsal iris (2/7 -29%) (Tsonis lab; unpublished) suggesting that FGFR-1 signaling is not sufficient for lens regeneration. To confirm that FGF activity is essential to lens regeneration, Hayashi and others also injected soluble FGF receptors to compete with endogenous receptors for FGF binding [19]. It was observed during FGFR2 (IIIc)/Fc (binding FGF 1,2,4, and 9) daily injections that lens regeneration was completely inhibited.…”

“…It was observed during FGFR2 (IIIc)/Fc (binding FGF 1,2,4, and 9) daily injections that lens regeneration was completely inhibited. However, when FGFR2(IIIb)/Fc (binding FGF 1,7, and 10) was injected, no effect on lens regeneration was observed [19].…”