Heparan Sulfate Proteoglycans: Orchestrators of Lens Biology, Development and Pathology

Abstract

Heparan sulfate proteoglycans (HSPGs) can be considered as the “dark matter” of the biological universe: a major regulatory cellular component for which specific functions are only beginning to be elucidated. Ubiquitous to all animal cells, HSPGs are a major component of the cell surface and extracellular matrix, where they serve as the versatile interface of cells with their environment through regulation of protein-protein interactions. This thesis investigates the role of HSPGs in regulating ocular lens biology and development. HSPGs have been found to regulate the signaling of growth factors and their distribution and interaction with receptors. This work identifies the specific HSPG expression profile of the lens, and elucidates their roles in growth factor mediated lens growth and pathology . Here we find that all HSPGs are expressed in the murine lens in unique spatiotemporal patterns throughout development, with HS-GAG being the predominant HSPG associated GAG in the postnatal and developing lens. The identification of specific HSPG core proteins in key functional lens regions, and the divergent expression patterns of closely related HSPGs, suggests that different HSPGs may differentially regulate growth factor signalling networks leading to specific biological events involved in lens growth and maintenance. The requirement of HS for lens cell EMT, combined with the differential expression of HS-GAG and specific HSPG core proteins in cataractous lenses suggests that changes in the selective patterns and interactions and activity of specific HSPGs may point to candidate targets for the regulation of fibrotic changes underpinning the pathogenesis of fibrotic cataract. By further characterising and specifically modulating these sulfated proteins, we hope to develop novel ways of regulating cell behaviour that will not only be relevant to lens biology and disease, but may extend to other growth factor-mediated pathologies.