Abstract
Fibroblast growth factor (FGF) signaling is necessary for both proliferation and differentiation of lens cells. However, the molecular mechanisms by which FGFs exert their effects on the lens remain poorly understood. In this study, we show that FGF-2 repressed the expression of lens-specific genes at the proliferative phase in primary cultured lens cells. Using transfected cells, we also found that the activity of L-Maf, a lens differentiation factor, is repressed by FGF/ERK signaling. L-Maf is shown to be phosphorylated by ERK, and introduction of mutations into the ERK target sites on L-Maf promotes its stabilization. The stable L-Maf mutant protein promotes the differentiation of lens cells from neural retina cells. Taken together, these results indicate that FGF/ERK signaling negatively regulates the function of L-Maf in proliferative lens cells and that stabilization of the L-Maf protein is important for lens fiber differentiation.
Highlights
Fibroblast growth factors (FGFs)1 regulate a diverse range of biological activities including adhesion, migration, proliferation, and differentiation
These results indicate that FGF/extracellular-signal regulated kinase (ERK) signaling negatively regulates the function of lens-specific Maf (L-Maf) in proliferative lens cells and that stabilization of the L-Maf protein is important for lens fiber differentiation
Morphological changes induced by FGF in fiber differentiation, such as cell elongation, are blocked by a specific inhibitor against ERK signaling in explant culture but FGF-induced -crystallin expression is not [28]
Summary
Fibroblast growth factors (FGFs) regulate a diverse range of biological activities including adhesion, migration, proliferation, and differentiation (reviewed in Ref. 3). A truncated form of FGF receptor (FGFR) lacking the cytoplasmic kinase domain inhibits fiber cell differentiation when expressed in transgenic mice under the control of a lens-specific promoter [7], and a secreted form of FGFR can cause a delay in fiber differentiation [9] Together, these studies implicate FGFs as bifunctional molecules that regulate both proliferation and differentiation of the lens cells. Mutations at either of these two sites caused an increased stability of the L-Maf protein, resulting in enhanced expression of ␦-crystallin These results indicate that FGF/ERK signaling controls terminal differentiation of the lens fiber cells through regulation of L-Maf stability
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