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H. Chen, L. Xie, L.W. Reneker; Overexpression of Insulin in the Lens of Transgenic Mice Inhibits Fiber Cell Maturation and Terminal Differentiation . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2409.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Insulin has been shown to induce or enhance fiber cell differentiation in chicken and rat lens explants respectively. The present study is to investigate the in vivo effects of insulin on lens cell proliferation and differentiation. Methods: Transgenic mice that overexpress human insulin in the lens were generated using either the mouse αA–crystallin promoter or the heterogenic Δ1–crystallin enhancer/αA–crystallin (ΔenαA) promoter. Transgene expression level was determined by in situ hybridization using riboprobes specific for the transgenes. Changes in lens cell proliferation and differentiation were analyzed by histology and immunohistochemistry. The expression patterns of the insulin–signaling components, including the insulin receptor (IR), insulin–like growth factor 1 receptor (IGF1R), and insulin receptor substrate–1 (IRS–1) in the lens, were investigated by in situ hybridizations. Results: We generated two transgenic lines with the αA–promoter and six with the ΔenαA promoter. All the transgenic mice developed cataracts with different degree of severity correlated with the expression levels of the transgene. Histologically, the lens epithelial cells in the transgenic mice appeared to be normal with no indication of premature elongation or expression of fiber cell–specific proteins such as ß–crystallin or CP49. Additionally, there was no significant change in cell proliferation in the transgenic lens judged by the bromodeoxyurindine (BrdU) incorporation index. These results suggest that increased insulin is not sufficient to induce either premature differentiation or overproliferation of the lens epithelial cells in transgenic mice. In contrast, fiber cells in the transgenic mice were disorganized and vacuolated, even though the expression patterns of ß– and γ–crystallins, and CP49 were not altered. Interestingly, fiber cell denucleation and intracellular organelle degradation were blocked in the transgenic lens. In situ hybridization showed that IR and IRS–1 are expressed in the differentiating fiber cells while IGF1R is mainly expressed in the lens epithelium, suggesting that overstimulating the insulin–signaling pathway in lens fiber cells may interfere with the maturation and terminal differentiation process in these cells. Conclusions: Insulin overexpression is not sufficient to either induce or enhance lens cell differentiation in the transgenic mice. In contrast, overstimulation of the insulin–signaling pathways in the lens may antagonize with the signals involved in the fiber cell maturation and terminal differentiation.
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