Growth factor signalling and regulation of lens cell differentiation

Abstract

Studies on explanted lens epithelial cells have been central to the identification of growth factor families that play key roles in determining the differentiated states of lens cells. In vitro models have shown that quiescent epithelial cells can be induced to differentiate down the normal fibre differentiation pathway by FGF, or induced to undergo an epithelial mesenchymal transition (EMT) that is a key feature of subcapsular cataracts (including PCO) by TGFß. Central to the generation of these divergent phenotypes is reorganisation of the lens cell cytoskeleton. Recent studies in our laboratory have identified key roles for the Wnt growth factor family in regulating the lens cell cytoskeleton. Transgenic mice that overexpress the Wnt signalling inhibitor, secreted frizzled‐related protein 2 (Sfrp2), specifically in the lens, develop cataract and microphthalmia and exhibit a severely disrupted lens cellular architecture. The epithelial sheet is reduced and disordered. The lens fibre compartment is severely disrupted and it is notable that fibres do not elongate and undergo directed cell migration to form sutures. This is reflected in the absence of aligned microtubules and disrupted expression/activity of components of Wnt/planar cell polarity (PCP) signalling cascades including small GTPases (Cdc42, Rac1 and RhoA) and phospho‐JNK. These results have highlighted an important role for Wnt/PCP signalling in orchestrating the development of the highly ordered lens cellular architecture.