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Jeroen R. Pasterkamp, Marten P. Smidt, J. Peter H. Burbach, ""

The neurotransmitter dopamine has just celebrated its 50th birthday. The discovery of dopamine as a neuronal entity in the late 1950’s and the notion that it serves in neurotransmission has been a milestone in the field of neuroscience research. This milestone marked the beginning of an era that explored the brain as an integrated collection of neuronal systems that one could distinguish on basis of neurotransmitter identities, and importantly, in which one started to be able to pinpoint the seat of brain disease.

The mesodiencephalic dopaminergic (mdDA) system, previously designated as midbrain dopaminergic system, has received much attention since its discovery. The initial identification of dopamine as a neurotransmitter in the central nervous system (CNS) and its relevance to psychiatric and neurological disorders have stimulated a plethora of neurochemical, pharmacological and genetic studies into the function of dopamine neurons and their projections. In the last decade, studies on gene expression and development have further increased the knowledge of this neuronal population and have unmasked a new level of complexity. The start of the molecular dissection of the mdDA system has been marked by the cloning and characterization of Nurr1 and Pitx3. These transcription factors were shown to have a critical function during mdDA development. These initial studies have been followed by the identification of many other proteins that have a crucial function in the creation of a dopamine neuron permissive region, induction of precursors, induction of terminal differentiation and finally maintenance of the mdDA neuronal pool. In addition, work showing that the historically distinguished regions of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA ) harbor molecularly distinct sets of neuronal groups with specific connectivity patterns has added a new layer of complexity to how mdDA neurons are generated and function in the adult CNS. The current challenge in the field of dopamine research is to characterize the full extent of molecular processes that underlie mdDA neuron programming and to translate these findings into viable approaches for embryonic stem (ES)-cell engineering as an ultimate treatment of degenerative diseases as Parkinson’s disease.

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