Fibroblast growth factor receptor signaling is essential for lens fiber cell differentiation

Abstract

The vertebrate lens provides an excellent model to study the mechanisms that regulate terminal differentiation. Although fibroblast growth factors (FGFs) are thought to be important for lens cell differentiation, it is unclear which FGF receptors mediate these processes during different stages of lens development. Deletion of three FGF receptors (Fgfr1-3) early in lens development demonstrated that expression of only a single allele of Fgfr2 or Fgfr3 was sufficient for grossly normal lens development, while mice possessing only a single Fgfr1 allele developed cataracts and microphthalmia. Profound defects were observed in lenses lacking all three Fgfrs. These included lack of fiber cell elongation, abnormal proliferation in prospective lens fiber cells, reduced expression of the cell cycle inhibitors p27(kip1) and p57(kip2), increased apoptosis and aberrant or reduced expression of Prox1, Pax6, c-Maf, E-cadherin and alpha-, beta- and gamma-crystallins. Therefore, while signaling by FGF receptors is essential for lens fiber differentiation, different FGF receptors function redundantly.

Deletion of Autophagy-related 5 (Atg5) and Pik3c3 Genes in the Lens Causes Cataract Independent of Programmed Organelle Degradation

“…4B), suggesting that autophagy was inhibited at this time point. This is in line with previous reports using MLR10-Cre transgenic mice (33,34), in which expression of Cre initiated around 10.5 dpc (20), and therefore Pik3c3 flox/flox ;MLR10-Cre mice can be used for functional analysis in both primary and secondary fiber cells as reported previously (33)(34)(35)(36). Immunoblot analysis of the lens confirmed the absence of Pik3c3 proteins and accumulation of polyubiquitinated proteins and p62 in the 0.5-dayold Pik3c3 flox/flox ;MLR10-Cre neonates (Fig.…”

Sprouty Is a Negative Regulator of Transforming Growth Factor β-Induced Epithelial-to-Mesenchymal Transition and Cataract

“…Given that FGF is known to promote ERK1/2 signaling in the lens (74) and has also been shown to exacerbate TGFβ-induced cataracts in vitro (90), one could speculate that negative regulation of FGF signaling by Spry in lens cells may suppress anterior subcapsular cataract formation. However, given the essential role of FGF in lens development (71), the observation that our hemizygous transgenic mice overexpressing Spry1 in the lens do not present a phenotype is inconsistent with such an interpretation, although this finding may again be attributed to an insufficient dosage of Spry1.…”

“…For immunofluorescent labeling of phosphorylated forms of ERK1/2 (pERK) or E-cadherin, hydrated tissue sections were first subjected to heatinduced (105°C) antigen retrieval in 10 mmol/L sodium citrate (pH 6) for 10 min, before cooling for 20 min at room temperature and application of 3% normal goat serum (71). The anti-phospho-ERK1/2 (1:100; Cell Signaling, Danvers, MA, USA) and E-cadherin (1:200; Invitrogen, Carlsbad, CA, USA) antibodies were subsequently applied overnight at 4°C and their binding was detected with a goat anti-rabbit Cy3-conjugated secondary antibody (diluted 1:200; Sigma).…”

FGF ligands of the postnatal mammary stroma regulate distinct aspects of epithelial morphogenesis

“…FGF signaling has been shown to regulate cell differentiation in various other contexts, including the differentiation of embryonic stem cells and lens fiber (Zhao et al, 2008;Stavridis et al, 2010). Interestingly, however, FGF2 treatment of mammary basal cells does not upregulate the expression of luminal markers or target genes of Notch signaling, which promotes luminal differentiation (Bouras et al, 2008;Yalcin-Ozuysal et al, 2010).…”