The factors for the early and late development of midbrain dopaminergic neurons segregate into two distinct evolutionary clusters

Midbrain dopaminergic neurons are responsible for several functions in the reward system, control of emotion, motivation, cognition, and motor behavior. A set of well-characterized transcription factors involved in specification, neurogenesis, and neuronal differentiation determines the fate of these neurons and modulates their survival and maintenance postnatally. Identifying novel molecular connections with these factors might, therefore, lead to a better understanding of physiology as well as dysfunction and degeneration of these neurons in Parkinson's disease. To explore the links between developmental pathways and to identify novel linkages, we examined the correlations of phylogenetic profiles of these factors with those of the entire human proteome. Our analysis revealed two distinct evolutionary pathways comprising the early and late developmental factors and new linkages with these developmental cascades. These results suggest an evolutionary scenario for the development of the midbrain and dopaminergic neurons, with potential novel links to the canonical and non-canonical functions of the transcription factors.