Frank J Lovicu, EH Shin, G Zhao,JWMcAvo
Normal lens cellular processes, such as cellproliferation and fibre differentiation are regulatedby growth factors in the eye, such as FGF, that inducevarious intracellular receptor tyrosine kinase (RTK)signalling pathways (e.g. MAPK/ERK1/2). Thesesignalling pathways are in turn tightly regulated byantagonists, including members of the Sprouty (Spry),Sef and Spred families. Deregulation of these mol-ecules in the lens, for example Spry, leads to aberrantlens development and growth, as well as a fibroticresponse, typical of TGFß-induced epithelial tomesenchymal transition (EMT) leading to cataract.Many forms of cataract develop from aberrant changesin lens epithelial cells induced by TGF-?. Here weattempt to unravel the signal transduction pathwaysinvolved in TGFß-induced EMT in the lens resulting in cataract.
Lens epithelial explants and geneticallymodified mice were used to modulate growth factorsignalling in the lens, and examine changes in lenscell behaviour. Lens tissues were characterized usinga range of histochemical and immunolabellingtechniques.
Loss of Spry specifically in the lens results infibrotic changes typical of an EMT leading to cataract.This EMT in situ was shown to be associated withderegulation of TGFß-signalling in the lens, supportedby the enhanced ability of cells deficient for Spry toundergo TGFß-induced EMT in vitro. Moreover,elevated levels of Spry in lens cells could effectivelyblock TGFß-mediated signalling, in turn blocking theTGFß-induced EMT and subsequent cataract in situ.
Enhanced TGFß-signalling in the lensthrough deregulation of Spry leads to lens pathology,indicating a key role for Spry in tightly regulating thesignalling processes essential for maintenance of lensstructure and function. By better understanding themolecular interactions leading to specific signallingpathways influenced by Spry in the lens, this mayserve to develop putative therapeutic agents for theprevention of cataract and/or fibrotic disease.