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Tammy So, Frank J Lovicu; IGF1 and EGF act synergistically to mediate lens fiber differentiation: a process dependent on FGFR-signaling. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4837.
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© ARVO (1962-2015); The Authors (2016-present)
Fibroblast growth factors (FGFs) are well established as primary inducers of fiber differentiation. In vitro studies have shown that a relatively high dose of FGF, comparable to vitreous humor, can induce lens fiber differentiation, as can a lower dose of FGF when combined with other ocular-derived growth factors, including platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF1) or epidermal growth factor (EGF). In the lens, these ‘co-growth factors’ act primarily as mitogens, and here we attempt to better characterise the role they play in lens fiber differentiation.
Rat lens epithelial explants were cultured with either bovine vitreous (v/v 50%), a high dose of FGF2 (100 ng/ml), IGF1 (50 ng/ml), EGF (5 ng/ml) or a combination of IGF1 and EGF (IGF1/EGF) for up to 5-days. A selective FGF receptor (FGFR) antagonist, SU5402, was used for inhibitory studies. Immunolabeling was used to localize fiber differentiation markers including β-crystallin and Prox1, as well as downstream intracellular signaling molecules including the phosphorylation of fibroblast receptor substrate 2 alpha (FR2Sα). Explants were also stained with periodic acid-Schiff to examine cell morphology.
IGF1 or EGF both stimulated lens cell proliferation; however, in combination, IGF1 and EGF synergistically induced a lens fiber differentiation response, with the development of multicellular lentoid bodies expressing β-crystallin and Prox1, similar to features of vitreous- and FGF-induced lens fiber differentiation. Most interestingly, IGF1/EGF-induced lens fiber differentiation was dependent on FGFR-signaling, with downstream phosphorylation of FR2Sα. This IGF1/EGF-fiber differentiation response was also inhibited in the presence of SU5402.
IGF1/EGF-induced lens fiber differentiation appears to directly involve FGFR-mediated signaling. This finding supports an essential requirement for FGFR-signaling in lens fiber differentiation, and highlights a putative novel mechanism for the activation of FGFR-signaling via other independent ocular growth factors, such as IGF1 and EGF.
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