The long-term objective of our research is to determine the critical sequence of cellular events that are important for the early development and synaptogenesis of human retinal photoreceptor cells. This is a logical extension of our current research on the migration of photoreceptors to the outer nuclear layer and their cell-to-cell contacts with the horizontal and Muller cells in normal and degenerating retina. Three major goals are proposed for this five-year study. The first goal is to document further, at the electron microscopic level, the nature and sequence of cell-to-cell contacts between Muller, photoreceptor and horizontal cells in the developing mouse retina. Monoclonal antibodies that react specifically with Muller or horizontal cells will serve as markers to study the early differentiation and contacts of these cells. This study will assess the suggested role of the horizontal cells in serving as """"""""pioneer"""""""" neurons in the formation of the outer synaptic layer. The hypothesis that the Muller cell plays an essential role in guiding photoreceptor cell migration will also be tested by destroying or damaging Muller cells during their development using the highly-specific glial toxin alpha-aminoadipic acid. The second goal is to evaluate the pattern of migration cones.; The retinal degenerative (rd) mouse (an animal with early onset photoreceptor degeneration) provides a convenient model system for this purpose. We will determine if observed clusters of degenerating, PNA-staining, cells in rd mice are cones that have failed to migrate and if these cells share a common, clonal lineage.; Neuroblasts will be micro- injected with retrovirus so that the clonally-related daughter cells will be labeled histochemically by the viral-induced marker Beta-D- galactosidase. These studies of labeled neuroblasts will not only help to define which cells die during development in the rd mouse retina, but will also provide a better understanding of the events leading to the normal development and organization of the photoreceptor cell layer. The third goal is to extend our findings from the developing mouse retina to the normal human retina. Because most central nervous system and retinal developmental defects from mutagens occur during critical periods of cell division or migration, a knowledge of the temporal sequence of these important events has direct medical significance for the well-being of the fetus. The ontogenic sequence of retinal cellular differentiation and organization derived from our studies on lower mammals will provide a framework for examining the differentiation of photoreceptor, horizontal and Muller cells during successive stages of human fetal development. These studies of comparative retinal differentiation will thus provide an outline of the critical periods of retinal development in humans.
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