The properties of stem cells have created the exciting possibility of producing high numbers of virtually any human cell type for cell replacement therapies. However, their implementation in Parkinson's disease therapy to replace the main cell type lost by the disease, dopamine-producing neurons (dopaminergic neurons), still remains a challenge because non-dopaminergic neurons are also generated and because the survival and/or functional properties of the cells are not optimal. We think that some of the reasons for these difficulties are: (1) that the molecular mechanisms regulating the generation of dopaminergic neurons are poorly understood; and (2) that some of the signals required for the complete maturation of human stem cells into dopaminergic neurons have not yet been applied to human stem cells. Our previous work has identified soluble signals involved in these processes. In the present project we plan to use such signals to develop novel protocols to enhance the yield of dopaminergic neurons and promote the integration and function of stem cell-derived dopaminergic neurons in rodent models of Parkinson's disease. In this project we will take advantage of the availability of tools, protocols and technology to: (1) Generate dopaminergic neurons from human embryonic and/or neural stem cells. (2) Examine their integration and function in animal models of Parkinson's disease. The ultimate goal will be to achieve long lasting behavioral recovery in rodent models of Parkinson's disease.