Abstract
Purpose: :
Numerous growth factors are known to maintain proper lens growth by regulating the proliferation of epithelial cells and their differentiation into precisely organised fibre cells. These growth factors induce such cellular responses by activating various intracellular receptor tyrosine kinase (RTK) signaling pathways that are negatively regulated by different inhibitory molecules, including members of the Sprouty (Spry) family. In our laboratory, Spry1 and Spry2 have been shown to be expressed in the lens, leading to the hypothesis that Spry may play a role in the regulation of lens epithelial cell proliferation and differentiation. We examined the effect of Sprouty on these cellular processes by overexpressing Spry1 and Spry2 in lens cells.
Methods: :
Transgenic mice overexpressing Spry1 (using the Δ-enhancer/αA-crstallin promoter) or Spry2 (using LeCre-mediated Spry2 gain-of-function) in the lens were generated. The lenses of these mice were characterised using a range of histochemical and immunolabelling techniques. Cells in lens epithelial explants overexpressing Spry were used to examine the responsiveness of lens cells to growth factor stimulation.
Results: :
Overexpression of Spry1 or Spry2 in the lens of transgenic mice showed similar phenotypes, including a reduced lens size with subsequent posterior lens capsule thinning and rupture. The reduced size of the lens may have resulted from a decreased rate of lens epithelial cell proliferation and/or reduced rate of secondary fiber differentiation. The ability of cells overexpressing Spry to differentiate in vitro was also compromised in response to FGF. Interestingly, the ability to influence normal differentiation of lens fiber cells did not appear to be dependent on the continued ability of cells to phosphorylate the MAPKs, ERK1/2.
Conclusions: :
The comparable phenotypes observed between Spry1 and Spry2 overexpression in the lens highlights the ability of different Sprys to negatively regulate similar signaling pathways in the lens. The exact signaling pathways influenced by Spry in the lens are still yet to be determined. Overall, Spry may serve to tightly regulate the signaling processes essential for maintenance of lens structure and function.
Keywords: transgenics/knock-outs • signal transduction • growth factors/growth factor receptors