Birth, life and death of dopaminergic neurons in the substantia nigra.

Understanding the ontogeny of A9 dopamine (DA) neurons is critical not only to determining basic developmental events that facilitate the emergence of the substantia nigra pars compacta (SNc) but also to the extraction and de novo generation of DA neurons as a potential cell therapy for Parkinson’s disease. Recent research has identified a precise window for DA cell birth (differentiation) in the ventral mesencephalon (VM) as well as a number of factors that may facilitate this process. However, application of these factors in vitro has had limited success in specifying a dopaminergic cell fate from undifferentiated cells, suggesting that other cell/molecular signals may as yet remain undiscovered. To resolve this, current work seeks to identify particularly potent and novel DA neuron differentiation factors within the developing VM specifically at the moment of ontogeny. Through such (past and present) studies, a catalog of proteins that play a pivotal role in the generation of nigral DA neurons during normal CNS development has begun to emerge. In the future, it will be crucial to continue to evaluate the critical developmental window where DA neuron ontogeny occurs, not only to facilitate our potential to protect these cells from degeneration in the adult brain but also to mimic the developmental environment in a way that enhances our ability to generate these cells anew either in vitro or in vivo. Here we review our present understanding of factors that are thought to be involved in the emergence of the A9 dopamine neuron group from the ventral mesencephalon.