During development of the nervous system an excessive number of synaptic connections are formed. During postnatal development supernumerary synapses are then removed by a synapse elimination process that is only poorly understood. One factor that greatly contributes to synapse elimination is pruning of axonal and dendritic arbors. We have identified novel molecules that regulate the growth and pruning of dendritic trees. Using organotypic slice cultures, virus-mediated gene transfer in vivo, and knock-out mouse models, we are analyzing how the function of these genes is controlled by extracellular signals, cell-cell interactions and neuronal activity. In these studies, we identified the Rho-GAP protein family of signaling proteins called chimaerins as key mediators of axonal repulsion. Chimaerins interact directly with activated EphA-receptors and in vivo analysis of chimaerin mutant mice revealed that loss of one chimaerin isoform phenocopies loss of EphA4 receptors in developing cortico-spinal projections. In ongoing studies we are focusing on the role of chimaerins and related signaling molecules in synapse elimination in the cerebellum, and in particular on the the regulation of chimaerin proteins by synaptic activity.
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