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F. J. Lovicu, Q. Wang, J. W. McAvoy; Vitreous-Induced Lens Fiber Cell Differentiation: Regulation by Multiple Growth Factors via ERK1/2 and PI3-K Signaling. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2784. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Different growth factors in the vitreous have been shown to influence lens fiber cell differentiation, with only FGF able to solely induce this process. Many of these growth factors act through receptor tyrosine kinases (RTK) which primarily signal through the MAPK/ERK1/2 and PI3-K/Akt pathways. The main aim of this study was to gain a better understanding of the specific role these growth factors (FGF, IGF, PDGF and EGF) play in vitreous-induced lens fiber differentiation, as well as identify the mode of ERK1/2 signaling involved in this process.
Using rat lens epithelial explants, immunofluorescence for fiber-specific crystallins was used to assess fiber differentiation. Western blotting was also employed to characterise the signaling (ERK1/2 & Akt) profiles induced by the growth factors. In addition, the above assays were repeated in the presence of specific inhibitors for RTKs and for ERK1/2 and PI-3K signaling.
A sustained (12-18 hr) ERK1/2 phosphorylation profile was associated with vitreous or any growth factor treatment able to induce lens fiber differentiation. A ligand-independent sustained activation of ERK1/2 (using Na3VO4) was also sufficient to induce cell elongation and crystallin accumulation. Although sustained ERK1/2 activation is associated with fiber differentiation, it was not sufficient; a short exposure (30 min) to FGF can also induce a sustained ERK1/2 phosphorylation profile but does not promote fiber differentiation. Blocking studies demonstrated a dependence of fiber differentiation on both ERK1/2 and/or PI3-K signaling, with a key role for FGF throughout this process.
A sustained ERK1/2 signaling profile over 12-18 hours is required but not sufficient to induce fiber differentiation, with continual ERK1/2 or alternative signaling pathways required for the progression of the fiber differentiation process. FGF was not sufficient to reproduce the effects of vitreous-induced cell signaling and fiber differentiation, indicating a role for other vitreal-derived growth factors in this process. By characterising the role of individual growth factors within the vitreous, we hope to identify the specific factors and the signaling pathways involved in the regulation of lens fiber differentiation in vivo.
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