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Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract.

ABSTRACT: Cell-cell interactions organize lens fiber cells into highly ordered structures to maintain transparency. However, signals regulating such interactions have not been well characterized. We report here that ephrin-A5, a ligand of the Eph receptor tyrosine kinases, plays a key role in lens fiber cell shape and cell-cell interactions. Lens fiber cells in mice lacking ephrin-A5 function appear rounded and irregular in cross-section, in contrast to their normal hexagonal appearance in WT lenses. Cataracts eventually develop in 87% of ephrin-A5 KO mice. We further demonstrate that ephrin-A5 interacts with the EphA2 receptor to regulate the adherens junction complex by enhancing recruitment of beta-catenin to N-cadherin. These results indicate that the Eph receptors and their ligands are critical regulators of lens development and maintenance.

SUBMITTER: Cooper MA

PROVIDER: S-EPMC2575469 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract.

Cooper Margaret A MA Son Alexander I AI Komlos Daniel D Sun Yuhai Y Kleiman Norman J NJ Zhou Renping R

Proceedings of the National Academy of Sciences of the United States of America 20081023 43

Cell-cell interactions organize lens fiber cells into highly ordered structures to maintain transparency. However, signals regulating such interactions have not been well characterized. We report here that ephrin-A5, a ligand of the Eph receptor tyrosine kinases, plays a key role in lens fiber cell shape and cell-cell interactions. Lens fiber cells in mice lacking ephrin-A5 function appear rounded and irregular in cross-section, in contrast to their normal hexagonal appearance in WT lenses. Cata ...[more]

PMID: 18948590

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Project description:The primary energy substrate of the lens is glucose and uptake of glucose from the aqueous humor is dependent on glucose transporters. GLUT1, the facilitated glucose transporter encoded by Slc2a1 is expressed in the epithelium of bovine, human and rat lenses. In the current study, we examined the expression of GLUT1 in the mouse lens and determined its role in maintaining lens transparency by studying effects of postnatal deletion of Slc2a1. In situ hybridization and immunofluorescence labeling were used to determine the expression and subcellular distribution of GLUT1 in the lens. Slc2a1 was knocked out of the lens epithelium by crossing transgenic mice expressing Cre recombinase under control of the GFAP promoter with Slc2a1loxP/loxP mice to generate Slc2a1loxP/loxP;GFAP-Cre+/0 (LensΔGlut1) mice. LensΔGlut1 mice developed visible lens opacities by around 3 months of age, which corresponded temporally with the total loss of detectable GLUT1 expression in the lens. Spectral domain optical coherence tomography (SD-OCT) imaging was used to monitor the formation of cataracts over time. SD-OCT imaging revealed that small nuclear cataracts were first apparent in the lenses of LensΔGlut1 mice beginning at about 2.7 months of age. Longitudinal SD-OCT imaging of LensΔGlut1 mice revealed disruption of mature secondary fiber cells after 3 months of age. Histological sections of eyes from LensΔGlut1 mice confirmed the disruption of the secondary fiber cells. The structural changes were most pronounced in fiber cells that had lost their organelles. In contrast, the histology of the lens epithelium in these mice appeared normal. Lactate and ATP were measured in lenses from LensΔGlut1 and control mice at 2 and 3 months of age. At 2 months of age, when GLUT1 was still detectable in the lens epithelium, albeit at low levels, the amount of lactate and ATP were not significantly different from controls. However, in lenses isolated from 3-month-old LensΔGlut1 mice, when GLUT1 was no longer detectable, levels of lactate and ATP were 50% lower than controls. Our findings demonstrate that in vivo, the transparency of mature lens fiber cells was dependent on glycolysis for ATP and the loss of GLUT1 transporters led to cataract formation. In contrast, lens epithelium and cortical fiber cells have mitochondria and could utilize other substrates to support their anabolic and catabolic needs.

Project description:A disintegrin and metalloprotease-10(ADAM10) promotes the metastasis of prostate cancer (PCa), but the specific mechanism is indistinct. Herein, DU145 cell lines with stable overexpression and knockdown of ADAM10 were constructed. We found that ectopic expression of ADAM10 not only significantly facilitated cell proliferation, migration, invasion, and inhibited apoptosis, but also could specifically hydrolyze ephrin-A5 and release the ephrin-A5 soluble ectodomain into extracellular media in vitro. These effects were reversed by ADAM10 depletion or treatment of GI254023X. Meanwhile, the co-location and physical interaction among EphA3, ephrin-A5, and ADAM10 were observed in PCa cells using immunofluorescence and immunoprecipitation techniques. Interestingly, overexpression of EphA3 exerted opposite effects in DU145 (ephrin-A5 + ) cells and PC-3 (ephrin-A5 ± ) cells. In addition, the pro-tumor function of EphA3 was reversed by the treatment with the exogenous ephrin-A5-Fc, which increased the phosphorylation level of EphA3 in PC-3 (ephrin-A5 ± ) cells. In nude mice, ADAM10 accelerated growth of the primary tumor, decreased the level of ephrin-A5 in the tumor tissue, but increased the level of ephrin-A5 in the peripheral blood, accompanied with an increase in the expression of CD31 and VEGF (vascular endothelial growth factor) in the tissue. What is more, the serum ephrin-A5 content of patients with metastatic PCa was significantly higher than that of the non-metastatic group (P < 0.05). The receiver operating characteristic curve(ROC) showed that the area under the curve(AUC) of serum ephrin-A5 as a marker of PCa metastasis was 0.843, with a sensitivity of 93.5% and a specificity of 75%. It is concluded that ADAM10-mediated ephrin-A5 shedding promotes PCa metastasis via transforming the role of EphA3 from ligand-dependent tumor suppressor to ligand-independent promoter, and ephrin-A5 in the blood can be used as a new biomarker for PCa metastasis.

Dataset Information

Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract.

Publications

Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract.

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