Final Report Summary - BRAINGAIN (NOVEL STRATEGIES FOR BRAIN REGENERATION)
In contrast to mammals, newts possess exceptional capacities among adult vertebrates to rebuild complex structures, such as the brain. Our goal is to bridge the gap in the regenerative outcomes between newts and mammals, particularly focusing on the regeneration of dopamine producing neurons, which play a central role in Parkinson’s disease. The project has reached the following major results. First, we generated novel databases that allows systematic comparisons of genes and their regulation between newts and mammals. We generated a reference transcriptome and inferred proteomes for two newt species, Notophthalmus viridescnse, and Pleurodeles waltl, and we also sequenced the genome of Pleurodeles waltl. These data provide key resources for identifying molecular components of adult neurogenesis in the newt brain and to highlight essential differences comparing newts and mammals. Second, we characterized neural stem cells in the adult newt brain in terms of their heterogeneity and in terms of how their fate is regulated at the molecular level. We subdivided neural stem cells into two molecularly distinguishable populations. We also identified that the production of reactive oxygen species plays an important role in neurogenesis in newts both during normal homeostasis conditions as well as during dopamine neuron regeneration. Furthermore, we showed that the evolutionarily conserved Notch signaling differentially regulates the activation of neural stem cells during homeostasis compared to injury induced regeneration. Third, we identified a novel cell population in the adult mammalian brain, which has the potential to give rise to dopamine producing neurons in the adult brain and showed that, similarly to newts, antagonizing dopamine receptor signaling enhances dopaminergic neurogenesis in the mammalian brain. The model was further validated in a culture of mouse embryonic stem cell-derived dopaminergic neurons. With these studies we demonstrated the feasibility of enhancing of midbrain dopamine neurogenesis in mammals based on results originally obtained in newts. These finding are particularly important for direct cross-species comparisons and we believe that these findings could provide the basis of novel regenerative therapies in the future.