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E.-H. H. Shin, J. Boros, J. W. McAvoy, M. L. Robinson, F. J. Lovicu; A Role for Sprouty 1 and 2 as Antagonists of Growth Factor Signaling in the Lens. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4347.
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Growth factors are known to maintain lens growth by regulating the proliferation of epithelial cells and their differentiation into precisely organised fiber cells. These growth factors induce such cellular responses by activating various receptor tyrosine kinase (RTK) signaling pathways. Such pathways are in turn negatively regulated by different inhibitory molecules, including members of the Sprouty (Spry) family. In our laboratory, Spry1 and Spry2 have been shown to be strongly expressed in the lens. This led to the hypothesis that Spry may play a role in regulating the different cellular responses displayed by lens cells in response to growth factors. The purpose of our current work was to identify a role for Sprouty by examining the effect of overexpressing or conditionally deleting Spry1 and/or 2 in the lens.
Transgenic mice overexpressing Spry1 or Spry2 in the lens were generated and characterised. In addition, mice conditionally deficient for Spry1 and/or 2 in the eye were generated using the established Cre transgenic lines. Whole eyes or lenses from these mice were compared to wild-type tissues using a range of histochemical and immunolabelling techniques.
The overexpression of Spry1 and Spry2 in the lens showed similar phenotypes, displaying impaired lens epithelial cell proliferation, disruption of the fiber cell maturation process, as well as loss of posterior lens capsule integrity. Interestingly, the deletion of Spry1 and/or Spry2 in the eye presented a phenotype similar to that seen when overexpressing Spry, including the disruption to both fiber cell differentiation and the posterior capsule. Moreover, lenses deficient for Spry1 or Spry1/Spry2 developed cataracts postnatally, characterised by the formation of anterior subcapsular fibrotic plaques.
Our overexpression studies indicate that Spry1 and Spry2 have overlapping inhibitory functions in the lens; however, a distinct differential role for each Spry is indicated when they are selectively targeted for deletion. This may be accounted for by the differing levels of compensation being provided by the different Sprys. Further evaluation of our lines of mice will be required to clarify this issue. Overall, the severity of lens pathology in the absence of Spry emphasises the need to tightly regulate growth factor signaling in the lens/eye in order to maintain normal lens structure and function.
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