de Iongh Lab ~ Introduction

We are interested in identifying molecules and mechanisms that regulate the behaviour of lens cells during development and in disease.

Growth factors

Several families of growth factors have been shown to play key roles in both normal and pathological lens development.

Past research has shown that fibroblast growth factors (FGFs) are key inducers of lens cell proliferation, migration and differentiation.

Members of the transforming growth factor-ß (TGFß) super-family have also been shown to have important roles lens development and pathology (cataract). Our studies show that the lens expresses receptors for several of these growth factors, including the activin, BMP and TGFß receptors. Using transgenic mice that express dominant-negative receptors we showed that TGFß signalling is important for late stages of fibre cell differentiation and survival during embryonic development. However, inappropriate activation of this pathway in lens epithelial cells causes the cells to undergo changes (epithelial to mesenchymal transition) that are characteristic of forms of human cataract. Thus, the functions of this signalling pathway are different in the two cell types (epithelial and fibre cells) of the lens. A major focus of our research is to investigate the functions of the different TGF-ß family members during development and cataract formation by manipulating their signalling pathways in transgenic mice.

Transgenic mice that over-express constitutively active TGFß1 (B,D) in the lens develop subcapsular cataracts. Images courtesy of Dr Frank Lovicu.

Formation of cataract in mouse lenses expressing dominant-negative TGFß receptors.

Recent results also show that the Wnt family of glycoproteins may function to signal in lens development via the Wnt/ß-catenin signalling pathway. We are currently using conditional gene mutation approaches to investigate the role of ß-catenin in the lens.

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Adhesion molecules

During both normal differentiation and cataract formation there are major changes in cell-to-cell and cell-to-extracellular matrix (ECM) interactions, which are mediated by cell adhesion molecules such as integrins and cadherins. Recent studies have shown that the lens expresses a unique repertoire of integrin subunits during development, which is regulated by growth factor signalling. During TGFß-induced cataract formation there is altered expression of integrin subunits, which strongly reflects changes in expression of extracellular matrix molecules in the cataractous plaque.

Current research is directed at understanding how signalling via growth factor receptors, in concert with adhesion molecules such as the integrins, regulate lens cell behaviours. In particular, we are interested in investigating how integrin signalling via integrin-linked kinase (ILK) and focal adhesion kinase (FAK) affects lens epithelial cell behaviour and their response to growth factors.