| Summary |
WNT1/beta-catenin signaling plays a crucial role in the generation of mesodiencephalic dopaminergic (mdDA) neurons including the Substantia nigra pars compacta (SNc) subpopulation, whose degeneration is a hallmark of Parkinson’s Disease (PD). However, the precise functions of WNT/beta-catenin signaling in this context remain unknown. Using mutant mice, primary ventral midbrain (VM) cells and pluripotent stem cells (mouse embryonic stem cells and induced pluripotent stem cells), we show that Dickkopf 3 (DKK3), a secreted glycoprotein that modulates WNT/beta-catenin signaling, is specifically required for the correct differentiation of a rostrolateral mdDA precursor subset into SNc DA neurons. Dkk3 transcription in the murine VM coincides with the onset of mdDA neurogenesis and is required for the maintenance of LMX1A and consequently PITX3 expression in rostrolateral mdDA precursors, without affecting the proliferation or specification of their progenitors. Treatment of primary VM cells or differentiating pluripotent stem cells with recombinant WNT1 and/or DKK3 proteins consistently increases the proportion of mdDA cells with SNc DA neuron identity and promotes their survival in vitro. The SNc DA pro-differentiation and pro-survival properties of DKK3, together with its known anti-tumorigenic effect, therefore make it an ideal candidate for the improvement of regenerative and neuroprotective strategies in the treatment of PD. |
