Elevated insulin signaling disrupts the growth anddifferentiation pattern of the mouse lens

[摘要] Purpose: Insulin and insulin-like growth factors (IGFs) are putativeregulators of cell proliferation and differentiation during lensdevelopment. Transgenic mice that overexpress IGF-1 in the lens havebeen previously described. To further understand the ocular functions ofthis growth factor family, the in vivo effects of insulin expression onlens development were investigated using transgenic mice.Methods: Expression of insulin receptor (IR) and IGF-1 receptor(IGF-1R) in mouse lens was examined by reverse-transcriptase-polymerasechain reaction (RT-PCR) and in situ hybridization. Transgenic mice thatoverexpress insulin in the lens were generated using two differentpromoters: a fiber-cell specific αA-crystallin (αA) promoterand a modified αA-promoter linked to the chicken δ1-crystallin enhancer (called the δenαA promoter). TheδenαA promoter is active in both lens epithelial and fibercells. The lens phenotypes were analyzed by histology andimmunohistochemistry. Protein expression was examined by westernblotting.Results: Normal mouse lenses express both the insulin receptor (IR)and the IGF-1 receptor (IGF-1R), and their expression is highest at thelens periphery where the germinative and transitional zones are located.In transgenic mice, insulin expression in the lens induced cataractformation. The severity of the cataracts reflected the level oftransgene expression, independent of the type of promoter used. Inseverely affected families, the spherical shape of the lens was alteredand the lenses were smaller than normal. Histological analysis showed noevidence of premature differentiation of the anterior epithelial cells.In contrast to the IGF-1 mice, insulin transgenic mice exhibited ananterior shift in the location of the germinative and transitionalzones, leading to a reduction of the lens epithelial compartment.Additional alterations included expansion of the lens transitional zone,variable nuclear positioning in the lens bow region, and inhibition offiber cell denucleation and terminal differentiation.Conclusions: Elevated intraocular insulin does not enhanceproliferation nor induce differentiation of mouse lens epithelial cells.Since an increase in IGF-1 causes a posterior shift of the lensgeminative and transitional zones, while an increase in insulin causesan anterior shift of these zones, our results suggest that these twogrowth factors may work together to control the location of thisstructural domain during normal lens development. Our data also suggestthat increased insulin-signaling activity in the lens can antagonize theendogenous signals that are responsible for fiber cell maturation andterminal differentiation.

[学科分类] 生物化学/生物物理