Engineering a dopaminergic phenotype in stem/precursor cells - Role of Nurr1, glia-derived signals, and Wnts

Recent results from clinical trials using fetal tissue grafts in patients with Parkinson's disease (PD) have indicated that current surgical strategies for dopamine cell replacement therapy need to be improved in order to achieve better functional integration of the grafts and to avoid dyskinesias. Previous studies using rich dopaminergic (DA) cell suspensions have provided proof-of-concept that PD patients can benefit from cell replacement therapy. Stem cells have been proposed as better candidates for cell replacement therapy in PD since they can be standardized, expanded, and engineered in vitro. Recent developments indicate that cell preparations enriched in DA neurons can be generated in vitro, but their functional integration in animal models of disease is still far from optimal. This is not entirely surprising considering our limited knowledge of the development of DA neurons and the reduced number of factors that have been implemented in stem cell differentiation protocols. This review will focus on three aspects of DA neuron development: (1) the function of Nurr1 and retinoid X receptors (RXR) in the differentiation of DA precursors and in the survival of DA neurons; (2) the role of glia in DA neurogenesis and the differentiation of DA precursors; and (3) the function of the Wnt family of lipoproteins in the proliferation and differentiation of DA precursors. A greater understanding of the cellular and molecular mechanisms that control DA neuron development, as well as their functional integration in vivo, are likely to ultimately contribute to the development of novel stem cell replacement therapies for PD.