Parkinson's disease is a result of degeneration of the midbrain dopaminergic (DA) neurons. In the treatment of Parkinson's disease, replacing lost neurons is a promising therapy. However, the progress in cell replacement therapy is hampered by the lack of understanding of how the deficient neural circuits in Parkinson's patients can be repaired, and consequently the inability to connect implanted neurons into appropriate neural circuits. The proposed studies aim at identifying molecules, which regulate the formation of these circuits. Specifically, two classes of molecules, slits and ephrins that guide nerve fibers during nervous system development, will be analyzed. Cultured dopaminergic neurons will be used to assess the ability of these molecules to guide the movement of axons, and mutant mice, in which these genes are specifically inactivated, will be used to reveal the roles slits and ephrins play during the development of the dopaminergic circuits. Information obtained from these studies can facilitate the design of novel treatment protocols to reconstruct proper neural circuits in the treatment of Parkinson's disease.