Interplay between Wnt signalling and SOX6 in the development of substantia nigra pars compacta (SNc) midbrain dopaminergic neurons

In Parkinson’s disease (PD), degeneration of substantia nigra pars compacta (SNc) midbrain dopaminergic (mDA) neurons causes motor impairments in patients suffering from this illness. Yet, the reasons behind the selective degeneration of neuronal subpopulations and the specific mechanisms triggering PD are still unknown. However, research in mice identified Sox6 as a possible intrinsic determinant of SNc mDA neurons and their vulnerability. This thesis aims to disclose whether Sox6 plays a role in the selective vulnerability of SNc mDA neurons and to study its implication in the development of mDA neurons. To achieve this objective, this thesis established two hESC platforms generating subpopulations of SNc-like Sox6+ and VTA-like Otx2+ mDA neurons that are vulnerable and resistant to parkinsonism toxins, respectively. One platform generates Sox6+mDA neurons by inhibiting Wnt signalling and was used to investigate the interplay between Sox6 and Wnt singalling. The other platform gives rise to this vulnerable subpopulation by overexpressing Sox6 and was used to determine potential Sox6 downstream targets. In addition, this thesis also characterised a new Sox6GFPCreERT mouse line which was used for Sox6 lineage tracing to better understand the role of this transcription factor in the development of mDA neurons in vivo. Thus, my work was able to determine cell culturing conditions that favoured the generation of hESC-derived SNc-like mDA neurons, demonstrated that low Wnt signalling levels promoted a SNc mDA neuronal fate and identified a possible mechanism by which Sox6 could make SNc mDA neurons vulnerable.