CELL-CELL INTERACTIONS IN DYSPLASTIC RETINAL MORPHOGEN

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The major objectives of this proposal are to investigate pathogenetic mechanisms of dysplastic retinal morphogenesis, taking advantage of an excellent animal model of this condition represented by a consistently reproducible form of the disorder occurring as a heritable disease in the English Springer Spaniel dog. These studies relate directly to the goals of the National Eye Institute as stated in Vision Research--A National Plan (1983- 1987) in which it is recommended that the study of animal models with developmental and hereditary disorders of the retina to definite biochemical defects and pathogenetic mechanisms be given high priority. The critical lesion process has its inception in affected canine fetuses between 49 and 50 days of gestation, bilaterally affecting the dorsal peripapillary retina. It is characterized by a notch-like inflexion of the sensory retina as its outer limiting membrane, focal loss of the outer limiting membrane, disorganized proliferation of neuroblasts within the subretinal space, the formation of folds and rosettes, and eventual local retinal detachment form retinal pigment epithelial cells. A combined morphologic and biochemical approach will be used to evaluate the role of cell surface changes in retinal dysplasia. We will evaluate the role of intercellular junctions particularly at the external limiting membrane, in normal and dysplastic morphogenesis, by using quantitative freeze-fracture methodology. In addition, changes in membrane structure and composition will be identified by examination of intramembranous particle (IMP) distribution and by the use of filipin, a polyen antibiotic capable of binding to cholesterol within membranes. Changes in intercellular junctions or membrane structure may lead to abnormalities in cell proliferation of cell death, which will also be evaluated. Cell surface glycoconjugates are also important for normal cell-cell adhesion, migration, and communication. We will examine the role, temporal or topographical changes in neural-cell adhesion molecules and other glycoconjugates may have in dysplastic morphogenesis. This project is expected to add new insight into the role of the cell surface and membrane component in normal and aberrant developmental processes.