Genetic control of rodent midbrain dopaminergic neuron development in the light of human disease

Dopamine-producing neurons in the mammalian midbrain have received considerable attention in recent years because of their involvement in diverse neurological and psychiatric human disorders such as Parkinson's Disease (PD), schizophrenia and addiction. Although the underlying pathogenic mechanisms of these disorders are far from being understood, it is meanwhile accepted that a combination of genetic predisposition and environmental factors lead to the disease state. More recent evidence also suggests that both neurological and psychiatric disorders result from early disturbances affecting the normal development of the mesencephalic dopaminergic (mesDA) neurons. Understanding the cues directing the generation of the different mesDA cell groups, the establishment of their proper connections within the brain and their maintenance in the adult are therefore also of great clinical interest. Rodents, and in particular the mouse, have served as the classical "surrogate" organism for these studies based on their phylogenetic relationship to humans, their relatively well characterized mesDA system on both the anatomical and physiological levels, and especially on the propensity of the mouse to genetic manipulation enabling the dissection of genetic pathways underlying the proper generation and maintenance of the mesDA system in this species. In the present review, we will summarize recent findings in the overall context of murine mesDA neuron development.