The lens transmits and focuses light onto the retina. To do this it needs to be transparent and to have appropriate refractive properties. This depends on the development and maintenance of a highly ordered cellular architecture.
The lens consists of two forms of cells encapsulated within a basement membrane; (i) elongated fibre cells, grow to several millimetres in length, and are precisely aligned to form a regularly packed spheroidal mass, and (ii) cuboidal epithelial cells form a single-layered sheet that covers the anterior surface of the fibres. 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 to the fibre mass throughout life.
We have focussed our attention on growth factors because of their importance in regulating cell fates in many diverse 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 & differentiation; responses that are induced in a progressive dose-dependent manner.
We have proposed that an anterior-posterior gradient of FGF in the eye determines lens polarity and growth patterns and testing this hypothesis continues to be a major area of research activity in our laboratory. In addition to FGF, we are actively exploring the differential mitogenic effects of other growth factors primarily as a means of identifying which of these is important for regulating lens cell proliferation in the eye. Our more recent studies have also identified molecules, including members of the Wnt and Frizzled gene families, as well as putative growth factor antagonists, that appear to be essential for maintenance of the lens epithelium, primarily serving to tightly regulate its structural and functional characteristics.
In addition to better understanding normal lens developmental biology, our growth factor studies have also helped us to gain insights into the molecular basis of the major lens pathology, cataract. We have shown that members of the transforming growth factor beta (TGFß) family induce aberrant growth and differentiation of lens 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 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 induces cataractous effects on the lens and most importantly how it is regulated in the eye. This information is fundamental to understanding the molecular basis of cataract and devising strategies for prevention.
Some of the projects currently under investigation in the laboratory include:
Normal Lens Biology
- Investigate and characterize the signalling pathways downstream of different growth factors to determine how they influence lens cell proliferation and/or fibre differentiation.
- Use lens epithelial explant cultures to identify specific factors that maintain the normal lens epithelial phenotypic characteristics including cell-cell and cell-matrix adhesion and communication.
- Investigate the role of signalling by members of the TGFß super-family during lens development. Further studies are being undertaken to examine the role of other TGFß family members (eg. BMPs) in lens development.
- Using lens epithelial explants and the characterisation of transgenic mice to determine the role of novel lens-specific genes (growth factor antagonists) thought to be involved in regulation of growth factor bioavailability.
Lens Pathology (Cataract)
- Using transgenic mouse models to further understand how TGFß induces and regulates cataract formation.
- Using lens epithelial explant cultures to determine how TGFß disrupts the normal lens signalling pathways and induces an epithelial-mesenchymal transition characteristic of cataract.
- Using electron microscopy and immunolabelling techniques to characterise the initiation and progression of cataract formation in mutant mouse models.