Defining mesodiencephalic dopaminergic neurons Identifying different levels of transcriptional control

The Hallmark of Parkinson’s disease is the selective degeneration of the dopaminergic (DA) neurons of the Substantia Nigra pars compacta (SNc). The SNc, together with the Ventral tegmental area (VTA) and the Retrorubral field (RrF), form the mesodiencephalic dopaminergic (mdDA) system, located in the ventral midbrain. The selective vulnerability of the DA neurons of the SNc has led to the hypothesis that the nuclei of the mdDA system are not only anatomically distinct, but also molecularly. Previous studies showed that each subset is dependent on a unique transcriptional program for their development and in this thesis we have investigated the influence of both transcription factors and epigenetic mechanisms on the development of mdDA neurons. Multiple transcription factors have already been identified to play a role in the development of mdDA neurons, including Lmx1b. Lmx1b has mostly been associated with the early specification of the midbrain area, however, we studied the role of Lmx1b in terminal differentiation and neuronal survival of mdDA neurons. Next to transcription factors, transcriptional regulation via epigenetics has also been implicated to be essential for the development of a multicellular organism. We have focused on the involvement of Polycomb group (PcG) protein EZH2 and CBX8 in the development of mdDA neurons. PcG protein have been associated with the regulation of developmental transitions, from proliferation to differentiation and from neurogenesis to gliogenesis. To determine whether EZH2 and CBX8 are involved in different stages of mdDA development we studied different mouse model, in which these proteins were genetically removed.