The role of developmental transcription factors in adult midbrain dopaminergic neurons

Abstract Introduction Mesodiencephalic dopamine neurons play crucial roles in the control of a variety of brain functions, including voluntary movement and behavioural processes such as mood, reward, and attention. Degeneration of mesodiencephalic dopaminergic neurons also represents one of the principal pathological features of Parkinson’s disease. Recent progress led to the identification of transcription factors that are expressed in dopaminergic progenitors and are required for their differentiation. The expression of some of these transcription factors persists into adulthood but their exact functions in postnatal and adult dopaminergic neurons remain puzzling. The objective of this review is to gather recent findings on the potential roles of Foxa1, Foxa2, Nurr1, Pitx3, Otx2, Lmx1a, Lmx1b, En1, and En2 in the maintenance of dopaminergic circuitry throughout adulthood. This maintenance appears to be underpinned by the continued action of developmental transcription factors. The loss of functional alleles of Foxa1/2, Nurr1, Pitx3, or En1/2 seriously impairs the survival dopaminergic neurons, affecting preferentially the subtantia nigra pars compacta. Moreover, for almost all transcription factors reviewed here, a genetic association to Parkinson’s disease has been established. Currently, it is unclear how exactly these developmental transcription factors contribute to the maintenance and survival of the dopaminergic system, but one possible mechanism could be related to transcriptional/translational regulation of mitochondrial bioenergetics and biogenesis. Conclusion This review suggests that developmental transcriptional networks are essential for maturity maintenance of mesodiencephalic dopaminergic neurons. Much remains to be done to dissect the effects of each developmental transcription factor on the functional properties of mDA neurons in adults.