Development and Engineering of Dopamine Neurons

The neurotransmitter dopamine has just celebrated its 50th birthday. The discoveryof dopamine as a neuronal entity in the late 1950 s and the notion that it servesin neurotransmission has been a milestone in the field of neuroscience research. Thismilestone marked the beginning of an era that explored the brain as an integratedcollection of neuronal systems that one could distinguish on basis of neurotransmitteridentities, and importantly, in which one started to be able to pinpoint the seatof brain disease.§The mesodiencephalic dopaminergic (mdDA) system, previously designated asmidbrain dopaminergic system, has received much attention since its discovery. Theinitial identification of dopamine as a neurotransmitter in the central nervous system(CNS) and its relevance to psychiatric and neurological disorders have stimulated aplethora of neurochemical, pharmacological and genetic studies into the function ofdopamine neurons and their projections. In the last decade, studies on gene expressionand development have further increased the knowledge of this neuronal populationand have unmasked a new level of complexity. The start of the molecular dissectionof the mdDA system has been marked by the cloning and characterization of Nurr1and Pitx3. These transcription factors were shown to have a critical function duringmdDA development. These initial studies have been followed by the identification ofmany other proteins that have a crucial function in the creation of a dopamine neuronpermissive region, induction of precursors, induction of terminal differentiation andfinally maintenance of the mdDA neuronal pool. In addition, work showing that thehistorically distinguished regions of the substantia nigra pars compacta (SNc) andventral tegmental area (VTA ) harbor molecularly distinct sets of neuronal groups withspecific connectivity patterns has added a new layer of complexity to how mdDAneurons are generated and function in the adult CNS. The current challenge in thefield of dopamine research is to characterize the full extent of molecular processesthat underlie mdDA neuron programming and to translate these findings into viableapproaches for embryonic stem (ES)-cell engineering as an ultimate treatment ofdegenerative diseases as Parkinson s disease.§The chapters presented in this book provide an overview of the different stagesthat are distinguished during mdDA neuronal development. Chapter 1 discusses thedopamine systems of the zebrafish, being a powerful model organism for geneticintervention on the developmental programming of neuronal systems. In Chapter2 an overview is presented of dopamine systems that are present in the vertebrateCNS. Chapters 3-6 discuss the early specification of dopamine precursors and theprograms that lead to terminal differentiation. In Chapters 7 and 8 the maintenanceof dopamine neurons is discussed with a special emphasis on neurotrophic support.The specific connectivity of the dopamine system and the axon guidance rules thatapply to developing dopamine neurons are described in Chapter 9. An overview ofES-cell engineering of dopamine neurons is presented in Chapters 10 and 11.§The research directed towards unraveling the molecular programming of mdDAneurons continues to be highly exciting. One may expect that novel biological principleswill continue to emerge from this population of neurons. In the near futurethe field as a whole will mature towards a more comprehensive understanding ofmdDA neuronal development and network integration, and will continue to applyknowledge of dopamine neuron development and function to the treatment of humandisease.