OCULAR DEVELOPMENT AND NEUROBIOLOGYGROUP
OCULAR DEVELOPMENT AND NEUROBIOLOGY: RESEARCH OVERVIEW
Group Leader :
Work in the Ocular Development and Neurobiology research group is mainly concerned with the basic cellular, developmental and molecular genetic mechanisms that underlie the formation of the eye, an organ that Darwin described as one of his “Organs of Extreme Perfection and Complication” in the Origin of Species.
Specifically, we are interested in the development and ageing of the ocular lens and retina. Both are classic systems in developmental biology (e.g. Hans Spemann was awarded the 1935 Nobel Prize for Physiology or Medicine in part because of his work on lens induction. Furthermore, the study of the development of these essential components of the eye is highly relevant to gaining improved insights in to blindness caused by diseases such as cataract and glaucoma.
We use a number molecular biology techniques to investigate gene expression including RT-PCR/QPCR, microarray analysis, Western blotting, immunofluoresence microscopy, laser scanning confocal microscopy, histology and manipulation of genes/proteins of interest in tissue and cell culture and in vivo.
Cataract is a clouding of the lens of the eye, which impedes the passage of light to the retina causing low vision or complete blindness. Cataract results from ageing of the lens and is also associated with mutations in genes essential for lens development. Cataract accounts for 48% of all blindness in the world affecting about 18 million people and is one of the priority eye diseases of the World Health Organisation (WHO). There is still no known means of preventing cataract and although it is quite successfully treatable by implanting artificial lenses in to the eye, in some cases this procedure is itself associated with complications, such as posterior capsule opacification (PCO) requiring further treatment.
The molecular basis of lens development, ageing and cataract:
We have been interested for a number of years in the development of the ocular lens. The lens is comprised of two cell types: the lens epithelium at the anterior, which contains a stem cell population, and the lens fibre cells, which are derived from the differentiation of lens epithelial cells (See Figure 1). In particular, we have been studying the development of the secondary lens fibres, which undergo a process of organelle loss, including loss of nuclei. This process is essential for lens transparency. In order to clear itself of organelles, the lens uses cell death or apoptosis signalling pathways and various proteases. It is becoming apparent that defects in this process can cause cataract. We are also interested in global changes in gene expression during lens development and cataract formation and have identified numerous genes, which we have deposited to the Gene Expression Omnibus (GEO) and in our array database (CARD). Using microarray analysis, we made the seminal discovery that haemoglobin subunits are expressed in the lens during development and maturation and are differentially regulated during cataract progression. Since the mature lens has no blood supply, this discovery suggests important physiological roles for haemoglobin subunits outside the erythroid lineage. We are also interested in using the lens to gain insights into molecules that regulate both cell proliferation and cell death, such as the tumour suppressor p53 and its regulators Mdm2 (see Figure 2) and Mdm4 as well as Tumour Necrosis Factor (TNF) family members and their receptors and inhibitors of apoptosis (IAPs), such as Survivin.
Glaucoma is a complex disease causing visual field loss due to degeneration and death of retinal ganglion cells (RGCs) and characteristic optic neuropathy. It is also one of the WHO’s priority eye diseases and is responsible for 12% of all global blindness and affects 4.5 million people worldwide. Little is known about how to prevent the onset of glaucoma. Treatment can lead to maintenance of sight given early diagnosis, but if it progresses irreversible blindness results.
The molecular basis of RGC development, ageing and death:
We are currently engaged in several projects studying the role of apoptosis signalling in the development, degeneration and death of RGCs. We are investigating the potential expression and function of inhibitors of apoptosis (IAPs): Birc2/IAP1, Birc3/Iap2, Birc4/Xiap, Birc5/Survivin, Birc6/Bruce and Birc7/livin and a family of proteases called caspases in RGC death during development and in dendrite remodelling and death during ageing of the retina. The results have implications for greater understanding of the role of these factors in retinal development, ageing and diseases. Furthermore, the retina is a particularly accessible part of the nervous system in which to gain insights into the underlying mechanisms of neurodegenerative diseases including glaucoma.
Imaging eye development:
Magnetic resonance imaging (MRI) to model early embryonic eye development and in collaboration with Dr Paula Murphy of the Developmental Biology Research Group we are exploring the utility of Optical Projection Tomography (OPT) for imaging and modelling eye development.
Corneal epithelium development and gene expression profiling:
We are also interested in corneal epithelium development and have used a microarray approach to identify genes differentially expressed during corneal development. We are mining these data for potential corneal stem cell markers.
Embryonic stem cell differentiation:
We have recently shown that haemoglobin subunits are expressed in the very early embryo before development of the vasculature and in embryonic stem (ES) cells differentiating into embryoid bodies (EBs) in culture prior to the formation of blood islands. I am also interested in ES cell neural differentiation.
See Collaborations for more details on these and other ongoing projects
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Last updated: Jun 09 2010.