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E. H. Shin, M. L. Robinson, M. A. Basson, G. Martin, J. W. McAvoy, F. J. Lovicu; Sprouty Prevents TGFβ-Induced Cataractogenesis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3816.
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Cataract, the loss of transparency of the lens, is one of the leading causes of blindness in the world. A common form is anterior subcapsular cataract (ASC), characterized by an epithelial-to-mesenchymal transition (EMT). Maintenance of the lens is achieved by growth factors and their respective receptor-mediated signaling pathways. Members of the Sprouty (Spry) family are negative regulators of such pathways. In our laboratory, Spry1 and Spry2 have previously been shown to be expressed in the lens, primarily in the lens epithelium. More recently, we have demonstrated that conditional deletion of Spry1, or Spry1&2 results in ASC formation. The purpose of our current study was to determine the molecular mechanisms in the absence of Spry leading to ASC formation. Furthermore, since ASC is a characteristic phenotype observed in TGFβ1 overexpressing lenses, we hypothesize that Spry1 overexpression will prevent or reduce ASC formation.
Mice conditionally deficient for Spry1 or Spry1&2 in the eye, or lens, were generated using the established LeCre or MLR10 transgenic Cre-lines, respectively. For the ASC rescue study, transgenic mice overexpressing Spry1 in the lens were crossed with mice overexpressing TGFβ1. Lenses from all mice were compared to wild-type (WT) tissues using a range of histochemical and immunolabelling techniques.
The deletion of Spry1 or Spry1&2 in the lens led to vacuolization of the epithelium and subsequent ASC formation. Moreover, the posterior lens capsule thinned and subsequently ruptured. Prior to ASC formation, there was aberrant (increased) activation of TGFβ signaling (increased labeling of pSmad2 and Snail) in lens epithelia of Spry-deficient lenses compared to WT lenses. When Spry1 was overexpressed in TGFβ1-overexpressing lenses, there was no evidence of ASC formation.
The development of ASC in Spry-deficient lenses suggests that Spry may play a protective role for the normal lens epithelium. This is supported by the ability of Spry to block ASC formation in TGFβ1 overexpressing lenses. Overall, Spry proteins in the lens may be important for negatively regulating the signaling pathways (including TGFβ signaling) required for maintenance of the normal lens epithelium, and may serve as a putative therapeutic agent for the prevention of ASC in situ.
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