Group Leaders: Professor John McAvoy and Professor Frank Lovicu
The lens transmits and focuses light onto the retina. To do this, it needs to be transparent with appropriate curvature/refractive properties. This depends on the development and maintenance of highly ordered cellular architecture.
The lens consists of two forms of cells encapsulated within a basement membrane;
Whilst the fibre cells make up the bulk of the lens and mostly determine its optical properties, epithelial cells play a key role in maintaining an appropriate physiological environment within the lens. In addition, the epithelium contains the ‘stem cells’ that proliferate, migrate and differentiate into the new fibres that are progressively added throughout life.
We have focused our attention on growth factors because of their importance in regulating cell fates in developmental systems. Using a unique lens epithelial explant culture system we have identified members of the FGF growth factor family as inducers of lens cell proliferation, migration and differentiation; responses that are induced in a progressive dose-dependent manner. Based on this we proposed that an anterior-posterior gradient of FGF determines lens polarity and growth patterns in vivo. There is now compelling evidence to support this model and a major thrust of our research activity is aimed at elucidating FGF-induced signalling pathways and details of their regulation. In a recent development we have shown that the Wnt-Frizzled/Planar cell polarity signalling pathway is critical for coordinating the alignment and orientation of fibres so that they come together to form the transparent, spheroidal structure we know as the lens.
Insights into the molecular basis of the major lens pathology, cataract, have also arisen from our growth factor studies. We have shown that members of the transforming growth factor beta (TGFß) family induce aberrant growth and differentiation of lens epithelial cells. This progressively leads to disruption of normal cellular architecture and opacification of the lens. Cataract is the most common cause of blindness in the world today. Although surgery is generally effective, in many countries it cannot keep pace with the growing demand. Moreover, complications such as aberrant growth and differentiation of lens epithelial cells left behind after cataract surgery (most commonly referred to as posterior capsule opacification), require further treatment and add to the cost of cataract management. Because of its clinical significance it is vital to understand how TGFß is regulated in the eye and how it induces cataractous effects on the lens. This information is fundamental to understanding the molecular basis of cataract and devising strategies for prevention. Our recent studies have identified several families of growth factor signalling regulators in the lens (Sefs, Sprys and Spreds) and current research is aimed at manipulating their expression in order to block the cataractous effects of TGFß.
In another line of research we are working towards devising strategies that could be used to promote normal differentiation of lens epithelial cells after cataract surgery. Using our knowledge of factors that promote epithelial to fibre differentiation we have shown that ‘mini-lenses’ can be generated from rat epithelial explants. From these studies we have also identified interactions between lens epithelial and fibre cells that activate intrinsic programs that result in the self-assembly of the two forms of lens cells into functional lens-like spheroidal structures. We are working to elucidate the molecular basis of these interactions because we feel this will provide the key to promoting regeneration of lens structure and function after cataract surgery.
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