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Title: The role of the tumour suppressor gene 'Pten' during retinal development
Author: Cantrup, Robert Thomas
Advisor: Schuurmans, Carol
Keywords: Animal Physiology;Biology--Cell;Genetics;Biology--Molecular;Neuroscience;Biology--Molecular
Issue Date: 17-Jul-2012
Abstract: The retina is central nervous system tissue in the back of the eye. It serves as the first level of sensory processing of the visual environment. All the cell types of the retina have been well characterized, and we understand its physiological functioning. Developmental neurobiologists are interested in factors that dictate events such as the proliferation of neural progenitors, the differentiation of neural cell types, the migration of cells to their final destination, and how new neurons form synaptic connections to generate the mature brain. The retina is an attractive tissue to study neurodevelopment as its accessibility and cellular makeup are advantageous to conduct genetic manipulations of these developmental processes. When this project was undertaken, little was understood about the retinal-specific role of the protein PTEN (phosphatase and tensin homologue), and the PI3-K (phosphatidylinositol 3-kinase) signaling pathway – known to be responsible for proliferation, differentiation, cell death, migration, and neuronal process growth/connectivity events in other parts of the developing nervous system. This thesis describes experiments where I deleted the Pten gene in the mouse retina using a conditional knockout (cKO) approach, and characterized many phenotypes that occurred both during early and late retinal development. During early retinal development, I found that Pten is required to regulate retinal progenitor cell proliferation and differentiation of a selective subset of retinal cells, specifically amacrine cells and photoreceptors. During later stages of retinal development, I describe other phenotypes in the Pten cKO retina. There is an expansion of the inner plexiform layer, with specific process disruptions. The spacing of Pten mutant horizontal and dopaminergic amacrine cells was also aberrant, as was the fasciculation patterns of dopaminergic amacrine and ganglion cell processes in the retinal tangential plane. In electroretinograms, irregular oscillatory potentials were observed in Pten mutants, suggesting asynchronous amacrine cell firing. In visual behaviour tests, some Pten mutant animals also displayed impairments. I also discovered a morphological abnormality in the Pten cKO retina, and an alteration in the subcellular distribution of the protein DSCAM within dopaminergic amacrine cells. These data reveal new insights into the role of Pten signaling in the regulation of retinal development.
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