The correct functioning of the nervous system is critically dependent upon the establishment of precise connections between neurons and their target cells. The initial development of the neuronal network typically occurs before neurons become functionally active, and thus is believed to be established by molecular guidance cues. After entering the target fields, each axon must find the correct target cells to form specific connections, guided by positional cues (target selection). Whereas the modes of target selection are relatively simple in the peripheral nervous system, many neuronal projections in the central nervous system show more complex, discontinuously-segregated, domain-to-domain patterns. The broad and long-term objective of this proposal is to elucidate the molecular mechanisms that establish these complex neuronal maps, by using the olivocerebellar projection (the neuronal projection from the inferior olive to the cerebellum) as a model system.In the proposed studies, the function of Eph receptors and ephrins in target selection of the chicken olivocerebellar system will be investigated. The central hypothesis to be tested is that Eph receptors and ephrins constitute domain-specific positional information in the olivocerebellar system, and that spatially accurate receptor-ligand interaction is essential to guide inferior olivary axons to their correct target domains. First, expression patterns of Eph receptors and ephrins in the developing cerebellum and inferior olive will be determined by RNA in situ hybridization and affinity probe in situ, and the relationship between their expression domains and the olivocerebellar mapping domains will be revealed by axon tracing experiments. Second, in vivo functions of Eph receptors and ephrins in the olivocerebellar target selection will be examined directly in embryos, by using a retrovirus-mediated gene expression system. Third, in vitro effects of ephrin-A2 on inferior olivary axons will be tested in established axon behavior assays, the membrane stripe assay and the growth cone collapse assay. Results from the proposed studies will provide novel insights to the molecular mechanisms that establish complex central neuronal pathways. In addition, since many congenital disorders affect the central nervous system including the cerebellar system, they will also provide essential information on the pathogenesis of such disorders
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