Replacing dopaminergic neurons is an attractive alternative in the treatment of Parkinson's disease (PD). However, a successful treatment relies not only on the introduction of new neurons, but also critically on the ability of these neurons to form appropriate axon connections. Consequently, it is of vital interest to understand how neural circuits involved in PD are constructed during development, which may provide clues for intervention in regenerating appropriate circuits. Our long-term objective is to elucidate molecular mechanisms underlying development of dopaminergic neural circuits, which are fundamental for motor control and cognition. Our preliminary studies suggest that the Eph family tyrosine kinase receptors and ligands play key roles in the development of dopaminergic projections to striatal targets, and led to the hypothesis that the Eph receptors and ligands prevent substantia nigra dopaminergic axons from projecting to inappropriate targets. To test this hypothesis, we propose experiments to (1) study developmental dynamics of midbrain dopaminergic axon targeting, (2) analyze biological effects of ephrins on dopamingerc axon growth in vitro using neuron culture techniques, and (3) elucidate biological functions of Eph receptors and ligands in vivo using transgenic and knockout animals. The information obtained from the proposed studies will be useful for therapeutic interventions in directing axons toward appropriate targets.