Through use of genomics and bioinformatics approaches we have identified many novel genes and alternative gene products that are expressed in human and animal model eye tissues. Several of these have been selected for functional analysis using a broad range of functional and structural approaches to determine their roles in the eye and their implications for normal vision and for disease. These include:? 1: Platelet-derived growth factor D (PDGFD) belongs to the PDGF/VEGF family. In the anterior segment PDGFD, it is localized to iris and ciliary body, whereas in the retina, it is restricted to the outer plexiform layer. We have shown that PDGFD has a key role in control of lens growth and that anti-PDGFD strongly inhibits lens epithelial cell proliferation This finding suggests a major in vivo role for PDGFD in the mechanisms of coordinated growth of eye tissues. Intervention in the PDGFD pathway in the eye, perhaps by antibody or blocking peptide, could be useful in the treatment of certain cataracts, including post-operative secondary cataract. PDGFD is also expressed in photoreceptors and in RPE, suggesting possible roles in controls of photoreceptors survival and control of retinal vascularization. A functional promoter of the PDGFD gene has been identified and correctly directs expression of a GFP reporter to eye tissues. A conditional knock out of PDGFD in mouse is nearing completion. ? 2: Lengsin is a novel member of the glutamine synthetase (GS) superfamily that is specific for the vertebrate eye lens. It has ATP-binding activity but, so far, no demonstrable enzyme activity. Lengsin is expressed specifically in the layer of terminally differentiating secondary fiber cells in which nuclei and other organelles are lost and cytoskeleton and intracellular junctions are reorganized. A knock out model of lengsin is completed and is currently in breeding for homozygosity. ? 3: Recent publications have shown an important role for complement factor H (CFH) in the development of age-related macular degeneration (AMD). We have constructed yeast 2-hybrod libraries for aged human RPE/choroid and retina. Using constructs for the AMD-related domain 7 of CFH as bait we have identified potentially important targets for CFH binding in human RPE/choroid. These are being further evaluated by techniques including surface plasmon resonance spectroscopy. Interaction of CFH with RPE/choroid proteins could have local effects on its role in the complement system and might provide opportunities for therapeutic intervention.
| Wyatt, Keith; Gao, Chun; Tsai, Jen-Yue et al. (2008) A role for lengsin, a recruited enzyme, in terminal differentiation in the vertebrate lens. J Biol Chem 283:6607-15 |
| Harding, Rachel L; Howley, Sinead; Baker, Lee J et al. (2008) Lengsin expression and function during zebrafish lens formation. Exp Eye Res 86:807-18 |
| Wyatt, Keith; White, Helen E; Wang, Luchun et al. (2006) Lengsin is a survivor of an ancient family of class I glutamine synthetases re-engineered by evolution for a role in the vertebrate lens. Structure 14:1823-34 |
| Wistow, Graeme (2006) The NEIBank project for ocular genomics: data-mining gene expression in human and rodent eye tissues. Prog Retin Eye Res 25:43-77 |
| Ray, Sugata; Gao, Chun; Wyatt, Keith et al. (2005) Platelet-derived growth factor D, tissue-specific expression in the eye, and a key role in control of lens epithelial cell proliferation. J Biol Chem 280:8494-502 |
