The rise and fall of mesodiencephalic dopaminergic neurons Molecular programming by transcription factors Engrailed 1, Pitx3, and Nkx2.9 during the development of mesodiencephalic neurons

The mid- and hindbrain harbor two essential monoaminergic neuronal populations: the mesodiencephalic dopaminergic (mdDA) neurons in the midbrain and the serotonergic (5HT) neurons in the hindbrain. Both systems innervate multiple regions in the forebrain and are involved in the guidance of our mood, motility and motivation guided behavior. The population of mdDA neurons can be divided in the substantia nigra (SNc) and the ventral tegmental area (VTA). An important difference between these dopaminergic nuclei is revealed during the evolution of Parkinson's Disease (PD). The mdDA neurons of the SNc are progressively lost, whereas the mdDA neurons of the VTA are (mostly) spared. The subsequent loss of dopaminergic signaling in the striatum results in tremors, rigidity and depression in patients suffering from PD.
We investigate the origin story of the mdDA neuron in order to understand the mdDA system in the healthy, adult brain as well as in the adult brain during pathological conditions. We examined the molecular pathway of transcription factors Engrailed 1, Pitx3 and Nkx2.9, that are required to code mdDA neurons. Furthermore, we aimed to unravel the molecular coding that define the molecular and functional differences between SN and VTA neurons. Together this work contributes to the general knowledge of the developing mdDA neurons and the sensitivity to programmed cells death that characterizes the SN subset of mdDA neurons.