The long term objectives of this project are to understand at the molecular level some of the genetic and epigenetic factors responsible for cell differentiation and interactions in the mammalian Central Nervous System. With this knowledge it will be possible to understand more fully a wide range of developmental disorders and degenerative diseases that affect the nervous system. We have defined a cell surface carbohydrate determinant that shows position-dependent expression in the developing retina, transient expression in a number of cortical regions and a developmentally regulated secondary modification in cerebellum. We have identified the structure of this molecule in retina and cortex and intend to test whether specific enzymes are rate- limiting in its biosynthesis. A variety of in vitro culture systems will be used to study the possible role of this molecule in regulating cell interactions and process migration. Available monoclonal antibodies, and others to be produced against growth comes from embryonic rat cerebral cortex, will be used to define molecules on these organelles. Molecules that are on all growth cones, and those that are restricted to growth cones of particular cell types, will be studies for their potential role in selective fasciculation and directional process outgrowth. One class of growth cone molecules that will be studied in detail are those responsible for interactions that trigger biochemical responses such as increases in synaptic vesicle membrane protein expression, related to synapse formation. The possible role of the membrane bound proto-oncogenes c-src and c-yes in linking cell surface interactions to changes in gene expression will be examined since they show striking correlative changes in level and activity during neural development. Finally, since many of the cell interactions being studied are accompanied by, or cause, alterations in gene activity, this proposal will study the similarities and differences in activation mechanisms of a set of genes expressed in photoreceptors at discrete times during retinal development. Together, the specific aims in this proposal represent a focussed effort to define and understand the function of molecules expressed on neural cells and their processes during important phases of growth and cell interaction.
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